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Difference between revisions of "Gnaiger 2020 BEC MitoPathways"

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[[File:CA15203MitoEAGLE.png|right|280px|link=http://www.mitoeagle.org/index.php/MitoEAGLE|CA15203 MitoEAGLE]]
{{Publication
{{Publication
 
|title=Gnaiger E (2020) Mitochondrial pathways and respiratory control. An introduction to OXPHOS analysis. 5<sup>th</sup> ed. https://doi.org/10.26124/bec:2020-0002
|title=Gnaiger E (2020) Mitochondrial pathways and respiratory control. An introduction to OXPHOS analysis. 5<sup>th</sup> ed. Bioenerg Commun 2020.2: 112 pp. [[doi:10.26124/bec:2020-0002]]
|info=Bioenerg Commun 2020.2:112 pp. [[File:OpenAccess-downloadPDF.png|240px|link=https://wiki.oroboros.at/images/e/ec/BEC_2020.2_doi10.26124bec2020-0002.pdf |Open Access pdf]] ''published online'' 2020-12-30
|info=[[File:OpenAccess-downloadPDF.png|240px|link=https://wiki.oroboros.at/images/e/ec/BEC_2020.2_doi10.26124bec2020-0002.pdf |Bioblast pdf]] ''Published online:'' 2020-Dec-30<br /><br />
<br /><br />
|authors=Gnaiger Erich
|authors=Gnaiger Erich
|year=2020
|year=BEC 2020.2
|journal=Bioenerg Commun
|journal=Bioenerg Commun
|abstract=Version 1 ('''v1''') '''2020-12-30''' [https://wiki.oroboros.at/images/e/ec/BEC_2020.2_doi10.26124bec2020-0002.pdf doi:10.26124/bec:2020-0002]
|abstract=[[File:BEC.png|25px|link=https://www.bioenergetics-communications.org/index.php/bec/article/view/gnaiger_2020_mitopathways]] [https://wiki.oroboros.at/images/e/ec/BEC_2020.2_doi10.26124bec2020-0002.pdf https://doi.org/10.26124/bec:2020-0002]


Did you know that keeping your mitochondria fit is essential for quality of life, brain and muscle function, and resistance against preventable, immunological, and age-related degenerative diseases?  
Did you know that keeping your mitochondria fit is essential for quality of life, brain and muscle function, and resistance against preventable, immunological, and age-related degenerative diseases?  
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It is now our responsibility to transfer the enthusiasm for innovation, reproducibility, and quality in science, and to translate mitochondrial research into visionary healthcare solutions.
It is now our responsibility to transfer the enthusiasm for innovation, reproducibility, and quality in science, and to translate mitochondrial research into visionary healthcare solutions.
<br><br>
|keywords=[[Q-junction]], [[MitoPedia: Respiratory states |Respiratory states]], [[MitoPedia: Respiratory control ratios |Flux control ratios]], [[Additivity]], [[Body mass excess]]
|keywords=[[Q-junction]], [[MitoPedia: Respiratory states |Respiratory states]], [[MitoPedia: Respiratory control ratios |Flux control ratios]], [[Additivity]], [[Body mass excess]]
|editor=Gnaiger E
|editor=Gnaiger E
|mipnetlab=AT Innsbruck Gnaiger E, AT Innsbruck Oroboros
|mipnetlab=AT Innsbruck Gnaiger E, AT Innsbruck Oroboros
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<br>
<br>


[[File:Gnaiger 2020 BEC MitoPathways.jpg|66px|left|link=https://www.bioenergetics-communications.org/index.php/Gnaiger_2020_BEC_MitoPathways|Gnaiger 2020 BEC MitoPathways]]
[[File:Gnaiger 2020 BEC MitoPathways.jpg|66px|left|link=https://www.bioenergetics-communications.org/index.php/bec/article/view/gnaiger_2020_mitopathways|Gnaiger 2020 BEC MitoPathways]]
= A guide through the chapters =
= A guide through the chapters =
<br>
<br>
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:::# '''[[#Chapter_1._Real-time_OXPHOS_analysis |Real-time OXPHOS analysis]]'''. — Richard Altmann’s bioblasts are the systematic unit of bioenergetics and chemiosmotic coupling studied in living cells and mitochondrial preparations. A rigorous understanding of mitochondrial respiratory control relies on a clear concept of metabolic states and rates, accurate measurement and normalization of oxygen flux, and analysis of mitochondrial pathways.
:::# '''[[#Chapter_1._Real-time_OXPHOS_analysis |Real-time OXPHOS analysis]]'''. — Richard Altmann’s bioblasts are the systematic unit of bioenergetics and chemiosmotic coupling studied in living cells and mitochondrial preparations. A rigorous understanding of mitochondrial respiratory control relies on a clear concept of metabolic states and rates, accurate measurement and normalization of oxygen flux, and analysis of mitochondrial pathways.
:::# '''Respiratory states and rates: coupling control'''. — A concept-driven terminology frames our perception of the meaning of respiratory states and rates, from ROUTINE respiration of living cells to the capacity of oxidative phosphorylation (OXPHOS) determined in mitochondrial preparations, electron transfer (ET) capacity, LEAK respiration, and the distinction of uncoupled, noncoupled, or dyscoupled respiration.
:::# '''Respiratory states and rates: coupling control'''. — A concept-driven terminology frames our perception of the meaning of respiratory states and rates, from ROUTINE respiration of living cells to the capacity of oxidative phosphorylation (OXPHOS) determined in mitochondrial preparations, electron transfer (ET) capacity, LEAK respiration, and the distinction of uncoupled, noncoupled, or dyscoupled respiration.
:::# '''Normalization of rate: flow, flux, and flux ratios'''. — ‘The challenges of measuring respiratory rate are matched by those of normalization’ ([[BEC 2020.1 doi10.26124bec2020-0001.v1 |Gnaiger et al 2000]]). The effect of metabolic control variables on flow or flux can be expressed by normalization for rate in a ''reference state'', and is evaluated relative to a ''background state''. The concept of flux control efficiency is based on principles of thermodynamics and is guided by statistical considerations, to remove the bias of the classical respiratory control ratio.
:::# '''Normalization of rate: flow, flux, and flux ratios'''. — ‘The challenges of measuring respiratory rate are matched by those of normalization’ ([https://doi.org/10.26124bec2020-0001.v1 Gnaiger et al 2000]). The effect of metabolic control variables on flow or flux can be expressed by normalization for rate in a ''reference state'', and is evaluated relative to a ''background state''. The concept of flux control efficiency is based on principles of thermodynamics and is guided by statistical considerations, to remove the bias of the classical respiratory control ratio.
:::# '''NADH-linked pathways through Complex CI: respiratory pathway control with pyruvate, glutamate, malate'''. — Substrate combinations feeding electrons into the ET system through NADH have been considered to reflect physiological respiratory states in mitochondrial preparations. These protocols ignored the importance of cataplerotic metabolite depletion in the tricarboxylic acid (TCA) cycle.
:::# '''NADH-linked pathways through Complex CI: respiratory pathway control with pyruvate, glutamate, malate'''. — Substrate combinations feeding electrons into the ET system through NADH have been considered to reflect physiological respiratory states in mitochondrial preparations. These protocols ignored the importance of cataplerotic metabolite depletion in the tricarboxylic acid (TCA) cycle.
:::# '''S-pathway through Complex CII, F-pathway through CETF, Gp-pathway through CGpDH'''. — Succinate as the substrate of CII is at a level comparable to NADH as the substrate for CI. Too many textbooks and publications propagate the error of comparing NADH in the N-pathway with FADH<sub>2</sub> in the S-pathway ― together with fumarate, FADH<sub>2</sub> is a product but not a substrate of CII.
:::# '''S-pathway through Complex CII, F-pathway through CETF, Gp-pathway through CGpDH'''. — Succinate as the substrate of CII is at a level comparable to NADH as the substrate for CI. Too many textbooks and publications propagate the error of comparing NADH in the N-pathway with FADH<sub>2</sub> in the S-pathway ― together with fumarate, FADH<sub>2</sub> is a product but not a substrate of CII.
:::# '''NS-pathway through Complexes CI & CII: convergent electron transfer at the Q-junction'''. — The term ‘electron transport chain’ is a misnomer in bioenergetics, conceiling the convergent pathway architecture of the electron transfer ''system'' (ETS). This has direct implications on the design of substrate-uncoupler-inhibitor titration (SUIT) protocols, for reconstitution of TCA cycle function, and sequential separation of branches of mitochondrial pathways for OXPHOS analysis.
:::# '''NS-pathway through Complexes CI & CII: convergent electron transfer at the Q-junction'''. — The term ‘electron transport chain’ is a misnomer in bioenergetics, conceiling the convergent pathway architecture of the electron transfer ''system'' (ETS). This has direct implications on the design of substrate-uncoupler-inhibitor titration (SUIT) protocols, for reconstitution of TCA cycle function, and sequential separation of branches of mitochondrial pathways for OXPHOS analysis.
:::# '''Additivity of convergent electron transfer'''. — OXPHOS capacity depends on the degree of additivity of pathways converging at the Q-junction. Paradoxically, current concepts on ''interaction'' do not agree whether to categorize incompletely additive effects as synergistic or antagonistic. A new mathematical definition of additivity bridges the gap between these apparently incompatible models of interaction.
:::# '''Additivity of convergent electron transfer'''. — OXPHOS capacity depends on the degree of additivity of pathways converging at the Q-junction. Paradoxically, current concepts on ''interaction'' do not agree whether to categorize incompletely additive effects as synergistic or antagonistic. A new mathematical definition of additivity bridges the gap between these apparently incompatible models of interaction.
:::# '''Protonmotive pressure and respiratory control'''. — Why is thermodynamics scary? The driving ''force'' of chemical reactions is confusingly called an energy (Gibbs ''energy''), whereas it is actually an isomorphic force, linked to the electric and chemical terms of the protonmotive force. The gas law represents chemical force and gas pressure. Flux-force relations are non-linear. Why should we consider Fick’s linear law of diffusion and protonmotive pressure in the control of flux?
:::# '''Protonmotive pressure and respiratory control'''. — Why is thermodynamics scary? The driving ''force'' of chemical reactions is confusingly called an energy (Gibbs ''energy''), whereas it is actually an isomorphic force, linked to the electric and chemical terms of the protonmotive force ''pmF''. The gas law represents chemical force and gas pressure. Flux-force relations are non-linear. Why should we consider Fick’s linear law of diffusion and protonmotive pressure in the control of flux?
::::::» [[BEC tutorial-Living Communications: pmF to pmP|'''BEC tutorial-Living Communications: ''pmF'' to ''pmP''''']]


[[File:Gnaiger 2020 BEC MitoPathways.jpg|left|66px|link=https://www.bioenergetics-communications.org/index.php/Gnaiger_2020_BEC_MitoPathways|Gnaiger 2020 BEC MitoPathways]]
[[File:Gnaiger 2020 BEC MitoPathways.jpg|left|66px|link=https://www.bioenergetics-communications.org/index.php/bec/article/view/gnaiger_2020_mitopathways|Gnaiger 2020 BEC MitoPathways]]
= Preface =
= Preface =
[[File:Blue book banner.jpg|right|310px]]
[[File:Blue book banner.jpg|right|310px]]
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:::: Mitochondrial physiology is part of our lives. Mitochondrial fitness — the capacity of oxidative phosphorylation (OXPHOS) — is essential for the quality of your life, for brain and muscle function, for resistance against preventable and age-related degenerative diseases. Evolutionary background, age, gender (sex), lifestyle, and environmental factors (EAGLE) determine mitochondrial fitness, which is OXPHOS capacity and multiple mitochondrial functions. Comprehensive OXPHOS analysis is vital for understanding your cells, vital for our health care systems, and vitally deserves reliability and reproducibility of analytical and diagnostic studies.
:::: Mitochondrial physiology is part of our lives. Mitochondrial fitness — the capacity of oxidative phosphorylation (OXPHOS) — is essential for the quality of your life, for brain and muscle function, for resistance against preventable and age-related degenerative diseases. Evolutionary background, age, gender (sex), lifestyle, and environmental factors (EAGLE) determine mitochondrial fitness, which is OXPHOS capacity and multiple mitochondrial functions. Comprehensive OXPHOS analysis is vital for understanding your cells, vital for our health care systems, and vitally deserves reliability and reproducibility of analytical and diagnostic studies.


:::: The ''Blue Book'' on ''Mitochondrial Pathways and Respiratory Control'' presents a fundamental introduction to OXPHOS analysis. It combines concepts of bioenergetics and biochemical pathways related to mitochondrial (mt) core energy metabolism and provides the basis for the substrate-uncoupler-inhibitor titration (SUIT) protocols in high-resolution respirometry, which have been established since publication of the first edition of MitoPathways in 2007 (Fig. 1).  
:::: The ''Blue Book'' on ''Mitochondrial Pathways and Respiratory Control'' presents a fundamental introduction to OXPHOS analysis. It combines concepts of bioenergetics and biochemical pathways related to mitochondrial (mt) core energy metabolism and provides the basis for the substrate-uncoupler-inhibitor titration (SUIT) protocols in high-resolution respirometry, which have been established since publication of the first edition of MitoPathways in 2007 (Figure 1).  


[[File:MiPNet12.01 HRR2007.jpg|right|300px|thumb|Fig. 2.]]
[[File:MiPNet12.01 HRR2007.jpg|right|300px|thumb|Figure 2.]]
:::: Application of SUIT protocols for real-time OXPHOS analysis is a component of metabolic phenotyping (Fig. 2). OXPHOS analysis extends conventional bioenergetics to the level of mitochondrial physiology for functional diagnosis in health and disease. The Oroboros O2k for HRR has the high signal stability and unrestricted flexibility of titrations suited for application of elementary and complex SUIT protocols.
:::: Application of SUIT protocols for real-time OXPHOS analysis is a component of metabolic phenotyping (Figure 2). OXPHOS analysis extends conventional bioenergetics to the level of mitochondrial physiology for functional diagnosis in health and disease. The Oroboros O2k for HRR has the high signal stability and unrestricted flexibility of titrations suited for application of elementary and complex SUIT protocols.


:::: Since 2007, research in mitochondrial physiology sparked a revolution of bioenergetics by experimental design that appreciates the convergent architecture of the electron transfer system (ETS) with multiple branches of mitochondrial pathways converging at the Q-junction, leading to a novel concept of additivity introduced in the new Chapter 7 of the ''Blue Book''. These advancements are documented by >1,000 reports listed under '[[NS-pathway control state]]' in MitoPedia. To study respiratory control at the Q-junction, SUIT protocols are applied with physiological substrate cocktails, particularly NADH-linked substrates (N) in combination with succinate (NS), fatty acids (FNS), and glycerophosphate (FNSGp), which have been introduced for the first time in the 1<sup>st</sup> edition of MitoPathways (2007).
:::: Since 2007, research in mitochondrial physiology sparked a revolution of bioenergetics by experimental design that appreciates the convergent architecture of the electron transfer system (ETS) with multiple branches of mitochondrial pathways converging at the Q-junction, leading to a novel concept of additivity introduced in the new Chapter 7 of the ''Blue Book''. These advancements are documented by >1 000 reports listed under '[[NS-pathway control state]]' in MitoPedia. To study respiratory control at the Q-junction, SUIT protocols are applied with physiological substrate cocktails, particularly NADH-linked substrates (N) in combination with succinate (NS), fatty acids (FNS), and glycerophosphate (FNSGp), which have been introduced for the first time in the 1<sup>st</sup> edition of MitoPathways (2007).


:::: Since then, ‘MitoPedia’ was initiated and the COST Action MitoEAGLE flies. 666 coauthors joined forces to present a harmonized nomenclature on Mitochondrial Physiology ([[BEC 2020.1 doi10.26124bec2020-0001.v1 |Bioenerg Commun 2020.1]]), with an emphasis on conceptual consistency for establishing a quality-controlled database on mitochondrial respiratory physiology. The 5th edition of MitoPathways gained from this collaboration. Many terms and symbols are simplified or presented in a more explicit form compared to the 2014 edition. Terms and iconic symbols develop meaning in context. Contextual meaning is best communicated by stories told in entertaining lectures, or by equations even if they turn off the most motivated student. Motivation is never enough. We need passion, persistence, resilience to transpose equations, terms and stories into the domain of personal experience, gaining perspective from perception to conception. The best scientific experience is the experiment driven by a hypothetical story written in clear words and forged into meaningful equations. This may provide a guideline to the critical discussion of the ergodynamic concept of the protonmotive force and chemiosmotic pressure, inspired by the ''Grey Book'' of Peter Mitchell and added as the new Chapter 8 of the ''Blue Book''.
:::: Since then, ‘MitoPedia’ was initiated and the COST Action MitoEAGLE flies. 666 coauthors joined forces to present a harmonized nomenclature on Mitochondrial Physiology ([https://doi.org/10.26124bec2020-0001.v1 Bioenerg Commun 2020.1]), with an emphasis on conceptual consistency for establishing a quality-controlled database on mitochondrial respiratory physiology. The 5th edition of MitoPathways gained from this collaboration. Many terms and symbols are simplified or presented in a more explicit form compared to the 2014 edition. Terms and iconic symbols develop meaning in context. Contextual meaning is best communicated by stories told in entertaining lectures, or by equations even if they turn off the most motivated student. Motivation is never enough. We need passion, persistence, resilience to transpose equations, terms and stories into the domain of personal experience, gaining perspective from perception to conception. The best scientific experience is the experiment driven by a hypothetical story written in clear words and forged into meaningful equations. This may provide a guideline to the critical discussion of the ergodynamic concept of the protonmotive force and chemiosmotic pressure, inspired by the ''Grey Book'' of Peter Mitchell and added as the new Chapter 8 of the ''Blue Book''.


:::: Mitochondria are the structural and functional elementary units of cell respiration. MitoPathways is an element of the Oroboros Ecosystem driven by high-resolution respirometry and shaping mitochondrial physiology. A mosaic evolves by combining the elements into a picture of modern mitochondrial respiratory physiology.  
:::: Mitochondria are the structural and functional elementary units of cell respiration. MitoPathways is an element of the Oroboros Ecosystem driven by high-resolution respirometry and shaping mitochondrial physiology. A mosaic evolves by combining the elements into a picture of modern mitochondrial respiratory physiology.  
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:::: Specific thanks is extended to Oroboros team members Luiza Cardoso, Cristiane Cecatto, Carolina Doerrier, Sabine Schmitt, Timea Komlódi, Zulfiya Orynbayeva, and Lucie Zdrazilova for critical reading and helpful suggestions on various chapters, and to Univ.-Prof. Dr. Markus Haltmeier (Applied Mathematics, Univ Innsbruck, Austria) for stimulating discussions on additivity (Chapter 7).
:::: Specific thanks is extended to Oroboros team members Luiza Cardoso, Cristiane Cecatto, Carolina Doerrier, Sabine Schmitt, Timea Komlódi, Zulfiya Orynbayeva, and Lucie Zdrazilova for critical reading and helpful suggestions on various chapters, and to Univ.-Prof. Dr. Markus Haltmeier (Applied Mathematics, Univ Innsbruck, Austria) for stimulating discussions on additivity (Chapter 7).


[[File:Gnaiger 2020 BEC MitoPathways.jpg|left|66px|link=https://www.bioenergetics-communications.org/index.php/Gnaiger_2020_BEC_MitoPathways|Gnaiger 2020 BEC MitoPathways]]
[[File:Gnaiger 2020 BEC MitoPathways.jpg|left|66px|link=https://www.bioenergetics-communications.org/index.php/bec/article/view/gnaiger_2020_mitopathways|Gnaiger 2020 BEC MitoPathways]]
= References =
= References =
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[[File:Gnaiger 2020 BEC MitoPathways.jpg|left|66px|link=https://www.bioenergetics-communications.org/index.php/Gnaiger_2020_BEC_MitoPathways|Gnaiger 2020 BEC MitoPathways]]
[[File:Gnaiger 2020 BEC MitoPathways.jpg|left|66px|link=https://www.bioenergetics-communications.org/index.php/bec/article/view/gnaiger_2020_mitopathways|Gnaiger 2020 BEC MitoPathways]]
= Chapters: References and notes =
= Chapters: References and notes =


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::::# Gnaiger E (2014) Mitochondrial pathways and respiratory control. 4<sup>th</sup> ed. Oroboros MiPNet Publications, Innsbruck:80 pp. - »[[Gnaiger 2014 MitoPathways|Bioblast link]]«
::::# Gnaiger E (2014) Mitochondrial pathways and respiratory control. 4<sup>th</sup> ed. Oroboros MiPNet Publications, Innsbruck:80 pp. - »[[Gnaiger 2014 MitoPathways|Bioblast link]]«
::::# Gnaiger E ed (2007) Mitochondrial pathways and respiratory control. 1<sup>st</sup> ed. Oroboros MiPNet Publications, Innsbruck:96 pp. - »[[Gnaiger 2007 MitoPathways|Bioblast link]]«
::::# Gnaiger E ed (2007) Mitochondrial pathways and respiratory control. 1<sup>st</sup> ed. Oroboros MiPNet Publications, Innsbruck:96 pp. - »[[Gnaiger 2007 MitoPathways|Bioblast link]]«
::::# Gnaiger E et al ― MitoEAGLE Task Group (2020) Mitochondrial physiology. Bioenerg Commun 2020.1. [[doi:10.26124/bec:2020-0001.v1]].
::::# Gnaiger E et al ― MitoEAGLE Task Group (2020) Mitochondrial physiology. Bioenerg Commun 2020.1. https://doi.org/bec:2020-0001.v1  


::::» [[MitoPedia: Terms and abbreviations]]
::::» [[MitoPedia: Terms and abbreviations]]


[[File:Gnaiger 2020 BEC MitoPathways.jpg|left|66px|link=https://www.bioenergetics-communications.org/index.php/Gnaiger_2020_BEC_MitoPathways|Gnaiger 2020 BEC MitoPathways]]
[[File:Gnaiger 2020 BEC MitoPathways.jpg|left|66px|link=https://www.bioenergetics-communications.org/index.php/bec/article/view/gnaiger_2020_mitopathways|Gnaiger 2020 BEC MitoPathways]]
[[File:Hydrogen ion circuit.jpg|right|300px|thumb|Fig. 1.1.]]
[[File:Hydrogen ion circuit.jpg|right|300px|thumb|Figure 1.1. Coupling in oxidative phosphorylation is mediated by the protonmotive force ''pmF''.]]
== Chapter 1. Real-time OXPHOS analysis ==
== Chapter 1. Real-time OXPHOS analysis ==


[[File:Gnaiger_2008_Fig.jpg|right|300px|thumb|Fig. 1.2.]]
[[File:Gnaiger_2008_Fig.jpg|right|300px|thumb|Figure 1.2.]]
=== References: 1. OXPHOS ===
=== References: 1. OXPHOS ===
:::# Altmann R (1894) Die Elementarorganismen und ihre Beziehungen zu den Zellen. Zweite vermehrte Auflage. Verlag Von Veit & Comp, Leipzig:160 pp, 34 Tafeln. - [[Altmann 1894 Verlag Von Veit & Comp |»Bioblast link«]]
:::# Altmann R (1894) Die Elementarorganismen und ihre Beziehungen zu den Zellen. Zweite vermehrte Auflage. Verlag Von Veit & Comp, Leipzig:160 pp, 34 Tafeln. - [[Altmann 1894 Verlag Von Veit & Comp |»Bioblast link«]]
:::# Dawson KD, Baker DJ, Greenhaff PL, Gibala MJ (2005) An accute decrease in TCA cycle intermediates does not affect aerobic energy delivery in contracting rat skeletal muscle. J Physiol 565:637-43. - [[Dawson 2005 J Physiol |»Bioblast link«]]
:::# Dawson KD, Baker DJ, Greenhaff PL, Gibala MJ (2005) An accute decrease in TCA cycle intermediates does not affect aerobic energy delivery in contracting rat skeletal muscle. - [[Dawson 2005 J Physiol |»Bioblast link«]]
:::# Garlid KD, Semrad C, Zinchenko V (1993) Does redox slip contribute significantly to mitochondrial respiration? In: Schuster S, Rigoulet M, Ouhabi R, Mazat J-P (eds) Modern Trends in Biothermokinetics. Plenum Press, New York, London:287-93. - [[Garlid 1993 BTK |»Bioblast link«]]
:::# Garlid KD, Semrad C, Zinchenko V (1993) Does redox slip contribute significantly to mitochondrial respiration? - [[Garlid 1993 BTK |»Bioblast link«]]
:::# Gibala 1998 Am J Physiol Endocrinol Metab|Gibala MJ, MacLean DA, Graham TE, Saltin B (1998) Tricarboxylic acid cycle intermediate pool size and estimated cycle flux in human muscle during exercise. Am J Physiol Endocrinol Metab 275:E235-42. - [[Gibala 1998 Am J Physiol Endocrinol Metab |»Bioblast link«]] - Concentrations of TCA cycle intermediates.
:::# Gibala MJ, MacLean DA, Graham TE, Saltin B (1998) Tricarboxylic acid cycle intermediate pool size and estimated cycle flux in human muscle during exercise. - [[Gibala 1998 Am J Physiol Endocrinol Metab |»Bioblast link«]] - Concentrations of TCA cycle intermediates.
:::# Gnaiger E (1983) Heat dissipation and energetic efficiency in animal anoxibiosis. Economy contra power. J Exp Zool 228:471-90. - [[Gnaiger 1983 J Exp Zool |»Bioblast link«]]
:::# Gnaiger E (1983) Heat dissipation and energetic efficiency in animal anoxibiosis. Economy contra power. - [[Gnaiger 1983 J Exp Zool |»Bioblast link«]]
:::# Gnaiger E (1993) Efficiency and power strategies under hypoxia. Is low efficiency at high glycolytic ATP production a paradox? In: Surviving Hypoxia: Mechanisms of Control and Adaptation. Hochachka PW, Lutz PL, Sick T, Rosenthal M, Van den Thillart G (eds) CRC Press, Boca Raton, Ann Arbor, London, Tokyo:77-109. - [[Gnaiger 1993 Hypoxia |»Bioblast link«]] - The Gibbs force of phorphorylation of ADP to ATP is ''F''<sub>ATP</sub> = 52 to 66 kJ/mol ATP under intracellular conditions.
:::# Gnaiger E (1993) Efficiency and power strategies under hypoxia. Is low efficiency at high glycolytic ATP production a paradox? - [[Gnaiger 1993 Hypoxia |»Bioblast link«]] - The Gibbs force of phorphorylation of ADP to ATP is ''F''<sub>ATP</sub> = 52 to 66 kJ/mol ATP under intracellular conditions.
:::# Gnaiger E (1993) Nonequilibrium thermodynamics of energy transformations. Pure Appl Chem 65:1983-2002. - [[Gnaiger 1993 Pure Appl Chem |»Bioblast link«]]
:::# Gnaiger E (1993) Nonequilibrium thermodynamics of energy transformations. - [[Gnaiger 1993 Pure Appl Chem |»Bioblast link«]]
:::# Gnaiger E (2003) Oxygen conformance of cellular respiration. A perspective of mitochondrial physiology. Adv Exp Med Biol 543:39-55. - [[Gnaiger 2003 Adv Exp Med Biol |»Bioblast link«]]
:::# Gnaiger E (2003) Oxygen conformance of cellular respiration. A perspective of mitochondrial physiology. - [[Gnaiger 2003 Adv Exp Med Biol |»Bioblast link«]]
:::# Gnaiger E (2008) Polarographic oxygen sensors, the oxygraph and high-resolution respirometry to assess mitochondrial function. In: Mitochondrial Dysfunction in Drug-Induced Toxicity (Dykens JA, Will Y, eds) John Wiley & Sons, Inc, Hoboken, NJ:327-52. - [[Gnaiger 2008 POS |»Bioblast link«]]
:::# Gnaiger E (2008) Polarographic oxygen sensors, the oxygraph and high-resolution respirometry to assess mitochondrial function. - [[Gnaiger 2008 POS |»Bioblast link«]]
:::# Gnaiger Erich (2020) Canonical reviewer's comments on: Bureau International des Poids et Mesures (2019) The International System of Units (SI) 9th ed. MitoFit Preprint Arch 2020.4 [[doi:10.26124/mitofit:200004]]. - [[File:CASE-cell count.png|right|300px|thumb|Fig. 1.4.]] [[File:CASE-cell count and elementary mass.png|right|300px|thumb|Fig. 1.5.]]  
:::# Gnaiger Erich (2020) Canonical reviewer's comments on: Bureau International des Poids et Mesures (2019) The International System of Units (SI) 9th ed. https://doi.org/doi:10.26124/mitofit:200004. - [[File:CASE-cell count.png|right|300px|thumb|Figure 1.4.]] [[File:CASE-cell count and elementary mass.png|right|300px|thumb|Figure 1.5.]]  
:::# Gnaiger Erich et al ― MitoEAGLE Task Group (2020) Mitochondrial physiology. Bioenerg Commun 2020.1. doi:10.26124/bec:2020-0001.v1. - [[BEC_2020.1_doi10.26124bec2020-0001.v1 |»Bioblast link«]]
:::# Gnaiger Erich et al ― MitoEAGLE Task Group (2020) Mitochondrial physiology. Bioenerg Commun 2020.1. https://doi.org/10.26124/bec:2020-0001.v1. https://doi.org/10.26124bec2020-0001.v1
:::# Gnaiger E, Kuznetsov AV (2002) Mitochondrial respiration at low levels of oxygen and cytochrome ''c''. Biochem Soc Trans 30:252-8. - [[Gnaiger 2002 Biochem Soc Trans |»Bioblast link«]]
:::# Gnaiger E, Kuznetsov AV (2002) Mitochondrial respiration at low levels of oxygen and cytochrome ''c''. - [[Gnaiger 2002 Biochem Soc Trans |»Bioblast link«]]
:::# Gnaiger E, Kuznetsov AV, Schneeberger S, Seiler R, Brandacher G, Steurer W, Margreiter R (2000b) Mitochondria in the cold. In: Life in the cold. (Heldmaier G, Klingenspor M, eds) Springer, Heidelberg, Berlin, New York:431-42. - [[Gnaiger 2000 Life in the Cold |»Bioblast link«]] – MiR05 as the basis of [[MiR06]].
:::# Gnaiger E, Kuznetsov AV, Schneeberger S, Seiler R, Brandacher G, Steurer W, Margreiter R (2000b) Mitochondria in the cold. - [[Gnaiger 2000 Life in the Cold |»Bioblast link«]] – MiR05 as the basis of [[MiR06]].
:::# Gnaiger E, Lassnig B, Kuznetsov AV, Margreiter R (1998) Mitochondrial respiration in the low oxygen environment of the cell: Effect of ADP on oxygen kinetics. Biochim Biophys Acta 1365:249-54. - [[Gnaiger 1998 Biochim Biophys Acta |»Bioblast link«]]
:::# Gnaiger E, Lassnig B, Kuznetsov AV, Margreiter R (1998) Mitochondrial respiration in the low oxygen environment of the cell: Effect of ADP on oxygen kinetics. - [[Gnaiger 1998 Biochim Biophys Acta |»Bioblast link«]]
:::# Gnaiger E, Lassnig B, Kuznetsov AV, Rieger G, Margreiter R (1998) Mitochondrial oxygen affinity, respiratory flux control, and excess capacity of cytochrome c oxidase. J Exp Biol 201:1129-39. - [[Gnaiger 1998 J Exp Biol |»Bioblast link«]]
:::# Gnaiger E, Lassnig B, Kuznetsov AV, Rieger G, Margreiter R (1998) Mitochondrial oxygen affinity, respiratory flux control, and excess capacity of cytochrome ''c'' oxidase. - [[Gnaiger 1998 J Exp Biol |»Bioblast link«]]
:::# Gueguen N, Lefaucheur L, Ecolan P, Fillaut M, Herpin P (2005) Ca<sup>2+</sup>-activated myosin-ATPases, creatine and adenylate kinases regulate mitochondrial function according to myofibre type in rabbit. J Physiol 564:723-35. - [[Gueguen 2005 J Physiol |»Bioblast link«]]
:::# Gueguen N, Lefaucheur L, Ecolan P, Fillaut M, Herpin P (2005) Ca<sup>2+</sup>-activated myosin-ATPases, creatine and adenylate kinases regulate mitochondrial function according to myofibre type in rabbit. - [[Gueguen 2005 J Physiol |»Bioblast link«]]
:::# Hatefi Y, Haavik AG, Fowler LR, Griffiths DE (1962) Studies on the electron transfer-pathway. XLII. Reconstitution of the electron transfer-pathway. J Biol Chem 237:2661-9. - [[Hatefi 1962 J Biol Chem |»Bioblast link«]]
:::# Hatefi Y, Haavik AG, Fowler LR, Griffiths DE (1962) Studies on the electron transfer-pathway. XLII. Reconstitution of the electron transfer-pathway. - [[Hatefi 1962 J Biol Chem |»Bioblast link«]]
:::# Kuznetsov AV, Schneeberger S, Seiler R, Brandacher G, Mark W, Steurer W, Saks V, Usson Y, Margreiter R, Gnaiger E (2004) Mitochondrial defects and heterogeneous cytochrome ''c'' release after cardiac cold ischemia and reperfusion. Am J Physiol Heart Circ Physiol 286:H1633–41. - [[Kuznetsov 2004 Am J Physiol Heart Circ Physiol |»Bioblast link«]] – Cytochrome ‘’c’’ test.
:::# Kuznetsov AV, Schneeberger S, Seiler R, Brandacher G, Mark W, Steurer W, Saks V, Usson Y, Margreiter R, Gnaiger E (2004) Mitochondrial defects and heterogeneous cytochrome ''c'' release after cardiac cold ischemia and reperfusion. - [[Kuznetsov 2004 Am J Physiol Heart Circ Physiol |»Bioblast link«]] – Cytochrome ''c'' test.
:::# Lane N (2005) Power, sex, suicide: Mitochondria and the meaning of life. Oxford University Press. 354 pp. - [[Lane 2005 Oxford Univ Press |»Bioblast link«]]  
:::# Lane N (2005) Power, sex, suicide: Mitochondria and the meaning of life. - [[Lane 2005 Oxford Univ Press |»Bioblast link«]]  
:::# Lemieux H, Blier PU, Gnaiger E (2017) Remodeling pathway control of mitochondrial respiratory capacity by temperature in mouse heart: electron flow through the Q-junction in permeabilized fibers. Sci Rep 7:2840, DOI:10.1038/s41598-017-02789-8. - [[Lemieux 2017 Sci Rep |»Bioblast link«]]
:::# Lemieux H, Blier PU, Gnaiger E (2017) Remodeling pathway control of mitochondrial respiratory capacity by temperature in mouse heart: electron flow through the Q-junction in permeabilized fibers. https://doi.org/10.1038/s41598-017-02789-8 - [[Lemieux 2017 Sci Rep |»Bioblast link«]]
:::# Mitchell P (1961) Coupling of phosphorylation to electron and hydrogen transfer by a chemi-osmotic type of mechanism. Nature 191:144-8. - [[Mitchell 1961 Nature |»Bioblast link«]]
:::# Mitchell P (1961) Coupling of phosphorylation to electron and hydrogen transfer by a chemi-osmotic type of mechanism. - [[Mitchell 1961 Nature |»Bioblast link«]]
:::# Mitchell P (1966) Chemiosmotic coupling in oxidative and photosynthetic phosphorylation. Glynn Research Ltd, Bodmin:192 pp. - [[Mitchell 2011 Biochim Biophys Acta |»Bioblast link«]] - ''The Grey Book'' 1. - '''"or, writing Δp for the P.M.F."''' (p. 35)
:::# Mitchell P (1966) Chemiosmotic coupling in oxidative and photosynthetic phosphorylation. Glynn Research Ltd, Bodmin:192 pp. - [[Mitchell 2011 Biochim Biophys Acta |»Bioblast link«]] - ''The Grey Book'' 1. - '''"or, writing Δp for the P.M.F."''' (p. 35)
:::# Mitchell P (1968) Chemiosmotic coupling and energy transduction. Glynn Research Ltd, Bodmin:111 pp. - ''The Grey Book'' 2.
:::# Mitchell P (1968) Chemiosmotic coupling and energy transduction. Glynn Research Ltd, Bodmin:111 pp. - ''The Grey Book'' 2.
:::# Mitchell P, Moyle J (1967) Respiration-driven proton translocation in rat liver mitochondria. Biochem J 105:1147-62. - [[Mitchell 1967 Biochem J |»Bioblast link«]]
:::# Mitchell P, Moyle J (1967) Respiration-driven proton translocation in rat liver mitochondria. Biochem J 105:1147-62. - [[Mitchell 1967 Biochem J |»Bioblast link«]]
:::# Mootha VK, Arai AE, Balaban RS (1997) Maximum oxidative phosphorylation capacity of the mammalian heart. Am J Physiol 272:H769-75. - [[Mootha 1997 Am J Physiol |»Bioblast link«]] – [Pi] <10 mM and [ADP] <0.4 mM limit OXPHOS in isolated heart mitochondria.
:::# Mootha VK, Arai AE, Balaban RS (1997) Maximum oxidative phosphorylation capacity of the mammalian heart. - [[Mootha 1997 Am J Physiol |»Bioblast link«]] – [Pi] <10 mM and [ADP] <0.4 mM limit OXPHOS in isolated heart mitochondria.
:::# Nicholson JK, Holmes E, Kinross JM, Darzi AW, Takats Z, Lindon JC (2012) Metabolic phenotyping in clinical and surgical environments. Nature 491:384-92. - [[Nicholson 2012 Nature |»Bioblast link«]]
:::# Nicholson JK, Holmes E, Kinross JM, Darzi AW, Takats Z, Lindon JC (2012) Metabolic phenotyping in clinical and surgical environments. - [[Nicholson 2012 Nature |»Bioblast link«]]
:::# Owen OE, Kalhan SC, Hanson RW (2002) The key role of anaplerosis and cataplerosis for citric acid cycle function. J Biol Chem 277:30409-12. - [[Owen 2002 J Biol Chem |»Bioblast link«]]
:::# Owen OE, Kalhan SC, Hanson RW (2002) The key role of anaplerosis and cataplerosis for citric acid cycle function. - [[Owen 2002 J Biol Chem |»Bioblast link«]]
:::# Pesta D, Gnaiger E (2012) High-resolution respirometry. OXPHOS protocols for human cells and permeabilized fibres from small biopisies of human muscle. Methods Mol Biol 810:25-58. - [[Pesta 2012 Methods Mol Biol |»Bioblast link«]] - >90 % saturation is reached only >5 mM ADP, yet previously few studies used such high [ADP] in permeabilized tissues and cells. - Oxygen limitation of respiration below air saturation.
:::# Pesta D, Gnaiger E (2012) High-resolution respirometry. OXPHOS protocols for human cells and permeabilized fibres from small biopisies of human muscle. - [[Pesta 2012 Methods Mol Biol |»Bioblast link«]] - >90 % saturation is reached only >5 mM ADP, yet previously few studies used such high [ADP] in permeabilized tissues and cells. - Oxygen limitation of respiration below air saturation.
:::# Puchowicz MA, Varnes ME, Cohen BH, Friedman NR, Kerr DS, Hoppel CL (2004) Oxidative phosphorylation analysis: assessing the integrated functional activity of human skeletal muscle mitochondria – case studies. Mitochondrion 4:377-85. - [[Puchowicz 2004 Mitochondrion |»Bioblast link«]] - Cytochrome ''c'' test.
:::# Puchowicz MA, Varnes ME, Cohen BH, Friedman NR, Kerr DS, Hoppel CL (2004) Oxidative phosphorylation analysis: assessing the integrated functional activity of human skeletal muscle mitochondria – case studies. - [[Puchowicz 2004 Mitochondrion |»Bioblast link«]] - Cytochrome ''c'' test.
:::# Rasmussen UF, Rasmussen HN (2000) Human quadriceps muscle mitochondria: A functional characterization. Mol Cell Biochem 208:37-44. - [[Rasmussen 2000 Mol Cell Biochem |»Bioblast link«]] - Cytochrome ''c'' test.
:::# Rasmussen UF, Rasmussen HN (2000) Human quadriceps muscle mitochondria: A functional characterization. - [[Rasmussen 2000 Mol Cell Biochem |»Bioblast link«]] - Cytochrome ''c'' test.
:::# Renner K , Amberger A, Konwalinka G, Gnaiger E (2003) Changes of mitochondrial respiration, mitochondrial content and cell size after induction of apoptosis in leukemia cells. Biochim Biophys Acta 1642:115-23. - [[Renner 2003 Biochim Biophys Acta |»Bioblast link«]] - [[File:Renner_2003_BBA-mt-density.jpg|right|300px|thumb|Fig.1.6A.]]
:::# Renner K , Amberger A, Konwalinka G, Gnaiger E (2003) Changes of mitochondrial respiration, mitochondrial content and cell size after induction of apoptosis in leukemia cells. - [[Renner 2003 Biochim Biophys Acta |»Bioblast link«]] - [[File:Renner_2003_BBA-mt-density.jpg|right|300px|thumb|Figure 1.6A.]]
:::# Rossignol R, Faustin B, Rocher C, Malgat M, Mazat JP, Letellier T (2003) Mitochondrial threshold effects. Biochem J 370:751-62. - [[Rossignol 2003 Biochem J |»Bioblast link«]]
:::# Rossignol R, Faustin B, Rocher C, Malgat M, Mazat JP, Letellier T (2003) Mitochondrial threshold effects. - [[Rossignol 2003 Biochem J |»Bioblast link«]]
:::# Saks VA, Veksler VI, Kuznetsov AV, Kay L, Sikk P, Tiivel T, Tranqui L, Olivares J, Winkler K, Wiedemann F, Kunz WS (1998) Permeabilised cell and skinned fiber techniques in studies of mitochondrial function in vivo. Mol Cell Biochem 184:81-100. - [[Saks 1998 Mol Cell Biochem |»Bioblast link«]] - The apparent ''K''<sub>m</sub> for ADP increases up to 0.5 mM in some permeabilized muscle fibres.
:::# Saks VA, Veksler VI, Kuznetsov AV, Kay L, Sikk P, Tiivel T, Tranqui L, Olivares J, Winkler K, Wiedemann F, Kunz WS (1998) Permeabilised cell and skinned fiber techniques in studies of mitochondrial function in vivo. - [[Saks 1998 Mol Cell Biochem |»Bioblast link«]] - The apparent ''K''<sub>m</sub> for ADP increases up to 0.5 mM in some permeabilized muscle fibres.
:::# Territo PR, Mootha VK, French SA, Balaban RS (2000) Ca<sup>2+</sup> activation of heart mitochondrial oxidative phosphorylation: role of the F0/F1-ATPase. Am J Physiol Cell Physiol 278:C423-35. - [[Territo 2000 Am J Physiol Cell Physiol |»Bioblast link«]]
:::# Territo PR, Mootha VK, French SA, Balaban RS (2000) Ca<sup>2+</sup> activation of heart mitochondrial oxidative phosphorylation: role of the F<sub>O</sub>/F<sub>1</sub>-ATPase. - [[Territo 2000 Am J Physiol Cell Physiol |»Bioblast link«]]


=== Notes: OXPHOS ===
=== Notes: OXPHOS ===
:::# [[Mitochondrial marker]]s
:::# [[Mitochondrial marker]]s


[[File:Gnaiger 2020 BEC MitoPathways.jpg|left|66px|link=https://www.bioenergetics-communications.org/index.php/Gnaiger_2020_BEC_MitoPathways|Gnaiger 2020 BEC MitoPathways]]
[[File:Gnaiger 2020 BEC MitoPathways.jpg|left|66px|link=https://www.bioenergetics-communications.org/index.php/bec/article/view/gnaiger_2020_mitopathways|Gnaiger 2020 BEC MitoPathways]]
[[File:States 1-2-3-4-5.jpg|right|300px|thumb]]
[[File:States 1-2-3-4-5.jpg|right|300px|thumb]]
[[File:RCR and OXPHOS coupling eff.jpg|right|300px|thumb]]
[[File:RCR and OXPHOS coupling eff.jpg|right|300px|thumb]]
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=== References: 2. States and rates ===
=== References: 2. States and rates ===
:::# Chance B, Williams GR (1955) Respiratory enzymes in oxidative phosphorylation. I. Kinetics of oxygen utilization. J Biol Chem 217:383-93. - [[Chance 1955 J Biol Chem-I |»Bioblast link«]]
:::# Chance B, Williams GR (1955) Respiratory enzymes in oxidative phosphorylation. I. Kinetics of oxygen utilization. - [[Chance 1955 J Biol Chem-I |»Bioblast link«]]
:::# Chance B, Williams GR (1955) Respiratory enzymes in oxidative phosphorylation. III. The steady state. J Biol Chem 217:409-27. - [[Chance 1955 J Biol Chem-III |»Bioblast link«]]
:::# Chance B, Williams GR (1955) Respiratory enzymes in oxidative phosphorylation. III. The steady state. - [[Chance 1955 J Biol Chem-III |»Bioblast link«]]
:::# Chance B, Williams GR (1956) The respiratory chain and oxidative phosphorylation. Adv Enzymol17:65-134. - [[Chance 1956 Adv Enzymol Relat Subj Biochem |»Bioblast link«]]
:::# Chance B, Williams GR (1956) The respiratory chain and oxidative phosphorylation. - [[Chance 1956 Adv Enzymol Relat Subj Biochem |»Bioblast link«]]
:::# Estabrook R (1967) Mitochondrial respiratory control and the polarographic measurement of ADP:O ratios. Meth Enzymol 10:41-7. - [[Estabrook 1967 Methods Enzymol |»Bioblast link«]]
:::# Estabrook R (1967) Mitochondrial respiratory control and the polarographic measurement of ADP:O ratios. - [[Estabrook 1967 Methods Enzymol |»Bioblast link«]]
:::# Gnaiger E (2001) Bioenergetics at low oxygen: dependence of respiration and phosphorylation on oxygen and adenosine diphosphate supply. Respir Physiol 128:277-97. - [[Gnaiger_2001_Respir Physiol |»Bioblast link«]]
:::# Gnaiger E (2001) Bioenergetics at low oxygen: dependence of respiration and phosphorylation on oxygen and adenosine diphosphate supply. - [[Gnaiger_2001_Respir Physiol |»Bioblast link«]]
:::# Gnaiger Erich et al ― MitoEAGLE Task Group (2020) Mitochondrial physiology. Bioenerg Commun 2020.1. doi:10.26124/bec:2020-0001.v1. - [[BEC 2020.1 doi10.26124bec2020-0001.v1| »Bioblast link«]]
:::# Gnaiger Erich et al ― MitoEAGLE Task Group (2020) Mitochondrial physiology. https://doi.org/10.26124/bec:2020-0001.v1. - [[BEC 2020.1 doi10.26124bec2020-0001.v1| »Bioblast link«]]
:::# Gnaiger E, Lassnig B, Kuznetsov AV, Margreiter R (1998) Mitochondrial respiration in the low oxygen environment of the cell: Effect of ADP on oxygen kinetics. Biochim Biophys Acta 1365:249-54. - [[Gnaiger_1998_Biochim Biophys Acta |»Bioblast link«]] - Oxygen kinetics is different in the LEAK state without adenylates (''L''<sub>N</sub>) and State 4 (LEAK state with ATP, ''L''<sub>N</sub>).
:::# Gnaiger E, Lassnig B, Kuznetsov AV, Margreiter R (1998) Mitochondrial respiration in the low oxygen environment of the cell: Effect of ADP on oxygen kinetics. - [[Gnaiger_1998_Biochim Biophys Acta |»Bioblast link«]] - Oxygen kinetics is different in the LEAK state without adenylates (''L''<sub>N</sub>) and State 4 (LEAK state with ATP, ''L''<sub>N</sub>).
:::# Gnaiger E, Méndez G, Hand SC (2000) High phosphorylation efficiency and depression of uncoupled respiration in mitochondria under hypoxia. Proc Natl Acad Sci U S A 97:11080-5. - [[Gnaiger 2000 Proc Natl Acad Sci U S A |»Bioblast link«]]
:::# Gnaiger E, Méndez G, Hand SC (2000) High phosphorylation efficiency and depression of uncoupled respiration in mitochondria under hypoxia. - [[Gnaiger 2000 Proc Natl Acad Sci U S A |»Bioblast link«]]
:::# König T, Nicholls DG, Garland PB (1969) The inhibition of pyruvate and Ls(+)-isocitrate oxidation by succinate oxidation in rat liver mitochondria. Biochem J 114:589-96. - [[Koenig 1969 Biochem J |»Bioblast link«]] - 3½ has been suggested to indicate an intermediate mitochondrial energy state somewhere between States 3 and 4. Would, therefore, State 4 be considered as being somewhere between State 3 and 5?
:::# König T, Nicholls DG, Garland PB (1969) The inhibition of pyruvate and Ls(+)-isocitrate oxidation by succinate oxidation in rat liver mitochondria. - [[Koenig 1969 Biochem J |»Bioblast link«]] - 3½ has been suggested to indicate an intermediate mitochondrial energy state somewhere between States 3 and 4. Would, therefore, State 4 be considered as being somewhere between State 3 and 5?
:::# Krumschnabel G, Eigentler A, Fasching M, Gnaiger E (2014) Use of safranin for the assessment of mitochondrial membrane potential by high-resolution respirometry and fluorometry. Methods Enzymol 542:163-81. - [[Krumschnabel 2014 Methods Enzymol |»Bioblast link«]]
:::# Krumschnabel G, Eigentler A, Fasching M, Gnaiger E (2014) Use of safranin for the assessment of mitochondrial membrane potential by high-resolution respirometry and fluorometry. - [[Krumschnabel 2014 Methods Enzymol |»Bioblast link«]]
:::# Singh Simon (1997) Fermat's last theorem. Fourth Estate, London 340 pp. - [[Singh 1997 Fourth Estate |»Bioblast link«]]
:::# Singh Simon (1997) Fermat's last theorem. Fourth Estate, London 340 pp. - [[Singh 1997 Fourth Estate |»Bioblast link«]]
[[File:EPL-net and excess.jpg|right|300px|thumb|Fig. 2.4.]]
[[File:EPL-net and excess.jpg|right|300px|thumb|Figure 2.4.]]
=== Notes: Coupling states ===
=== Notes: Coupling states ===
::::'''»''' [[MitoPedia: Respiratory states]] [[Image:P.jpg|link=OXPHOS capacity|OXPHOS]] [[Image:R.jpg|link=ROUTINE respiration|ROUTINE]] [[Image:E.jpg|link=ET capacity|ET capacity]] [[Image:L.jpg|link=LEAK respiration|LEAK]] - [[Image:ROX.jpg|link=Residual oxygen consumption|ROX]]
::::'''»''' [[MitoPedia: Respiratory states]] [[Image:P.jpg|link=OXPHOS capacity|OXPHOS]] [[Image:R.jpg|link=ROUTINE respiration|ROUTINE]] [[Image:E.jpg|link=ET capacity|ET capacity]] [[Image:L.jpg|link=LEAK respiration|LEAK]] - [[Image:ROX.jpg|link=Residual oxygen consumption|ROX]]
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:::# H<sup>+</sup> translocation through pumps is shown by dotted arrows across the mtIM.
:::# H<sup>+</sup> translocation through pumps is shown by dotted arrows across the mtIM.


[[File:Gnaiger 2020 BEC MitoPathways.jpg|left|66px|link=https://www.bioenergetics-communications.org/index.php/Gnaiger_2020_BEC_MitoPathways|Gnaiger 2020 BEC MitoPathways]]
[[File:Gnaiger 2020 BEC MitoPathways.jpg|left|66px|link=https://www.bioenergetics-communications.org/index.php/bec/article/view/gnaiger_2020_mitopathways|Gnaiger 2020 BEC MitoPathways]]
== Chapter 3. Normalization of rate: flow, flux, and flux ratios ==
== Chapter 3. Normalization of rate: flow, flux, and flux ratios ==


=== References: 3. Normalization ===
=== References: 3. Normalization ===
:::# Aguirre E, Rodríguez-Juárez F, Bellelli A, Gnaiger E, Cadenas S (2010) Kinetic model of the inhibition of respiration by endogenous nitric oxide in intact cells. Biochim Biophys Acta 1797:557-65. - [[Aguirre 2010 Biochim Biophys Acta |»Bioblast link«]] - Tables 3.1 and 3.2: HEK 293
:::# Aguirre E, Rodríguez-Juárez F, Bellelli A, Gnaiger E, Cadenas S (2010) Kinetic model of the inhibition of respiration by endogenous nitric oxide in intact cells. - [[Aguirre 2010 Biochim Biophys Acta |»Bioblast link«]] - Tables 3.1 and 3.2: HEK 293
:::# Chance B, Williams GR (1955) Respiratory enzymes in oxidative phosphorylation. I. Kinetics of oxygen utilization. J Biol Chem 217:383-93. - [[Chance 1955 J Biol Chem-I |»Bioblast link«]]
:::# Chance B, Williams GR (1955) Respiratory enzymes in oxidative phosphorylation. I. Kinetics of oxygen utilization. - [[Chance 1955 J Biol Chem-I |»Bioblast link«]]
:::# Chance B, Williams GR (1955) Respiratory enzymes in oxidative phosphorylation. III. The steady state. J Biol Chem 217:409-27. - [[Chance 1955 J Biol Chem-III |»Bioblast link«]]
:::# Chance B, Williams GR (1955) Respiratory enzymes in oxidative phosphorylation. III. The steady state. - [[Chance 1955 J Biol Chem-III |»Bioblast link«]]
:::# Doerrier C, Garcia-Souza LF, Krumschnabel G, Wohlfarter Y, Mészáros AT, Gnaiger E (2018) High-Resolution FluoRespirometry and OXPHOS protocols for human cells, permeabilized fibers from small biopsies of muscle, and isolated mitochondria. Methods Mol Biol 1782:31-70. - [[Doerrier 2018 Methods Mol Biol |»Bioblast link«]]
:::# Doerrier C, Garcia-Souza LF, Krumschnabel G, Wohlfarter Y, Mészáros AT, Gnaiger E (2018) High-Resolution FluoRespirometry and OXPHOS protocols for human cells, permeabilized fibers from small biopsies of muscle, and isolated mitochondria. - [[Doerrier 2018 Methods Mol Biol |»Bioblast link«]]
:::# Gnaiger E (2001) Bioenergetics at low oxygen: dependence of respiration and phosphorylation on oxygen and adenosine diphosphate supply. Respir Physiol 128:277-97. - [[Gnaiger_2001_Respir Physiol |»Bioblast link«]]
:::# Gnaiger E (2001) Bioenergetics at low oxygen: dependence of respiration and phosphorylation on oxygen and adenosine diphosphate supply. - [[Gnaiger_2001_Respir Physiol |»Bioblast link«]]
:::# Hütter E, Renner K, Pfister G, Stöckl P, Jansen-Dürr P, Gnaiger E (2004) Senescence-associated changes in respiration and oxidative phosphorylation in primary human fibroblasts. Biochem J 380:919-28. - [[Huetter 2004 Biochem J |»Bioblast link«]] - Tables 3.1 and 3.2: fibrolasts; Figure 3.1.
:::# Hütter E, Renner K, Pfister G, Stöckl P, Jansen-Dürr P, Gnaiger E (2004) Senescence-associated changes in respiration and oxidative phosphorylation in primary human fibroblasts. - [[Huetter 2004 Biochem J |»Bioblast link«]] - Tables 3.1 and 3.2: fibrolasts; Figure 3.1.
:::# Hütter E, Unterluggauer H, Garedew A, Jansen-Dürr P, Gnaiger E (2006) High-resolution respirometry - a modern tool in aging research. Exp Gerontol 41:103-9. - [[Huetter 2004 Biochem J |»Bioblast link«]]
:::# Hütter E, Unterluggauer H, Garedew A, Jansen-Dürr P, Gnaiger E (2006) High-resolution respirometry - a modern tool in aging research. - [[Huetter 2004 Biochem J |»Bioblast link«]]
:::# Renner K, Amberger A, Konwalinka G, Gnaiger E (2003) Changes of mitochondrial respiration, mitochondrial content and cell size after induction of apoptosis in leukemia cells. Biochim Biophys Acta 1642:115-23. - [[Renner 2003 Biochim Biophys Acta |»Bioblast link«]] - Tables 3.1 and 3.2: CEM
:::# Renner K, Amberger A, Konwalinka G, Gnaiger E (2003) Changes of mitochondrial respiration, mitochondrial content and cell size after induction of apoptosis in leukemia cells. - [[Renner 2003 Biochim Biophys Acta |»Bioblast link«]] - Tables 3.1 and 3.2: CEM
:::# Stadlmann S, Renner K, Pollheimer J, Moser PL, Zeimet AG, Offner FA, Gnaiger E (2006) Preserved coupling of oxidative phosphorylation but decreased mitochondrial respiratory capacity in IL-1ß treated human peritoneal mesothelial cells. Cell Biochem Biophys 44:179-86. - [[Stadlmann 2006 Cell Biochem Biophys |»Bioblast link«]]
:::# Stadlmann S, Renner K, Pollheimer J, Moser PL, Zeimet AG, Offner FA, Gnaiger E (2006) Preserved coupling of oxidative phosphorylation but decreased mitochondrial respiratory capacity in IL-1ß treated human peritoneal mesothelial cells. - [[Stadlmann 2006 Cell Biochem Biophys |»Bioblast link«]]


{{Template:Keywords: Coupling control}}
{{Template:Keywords: Coupling control}}
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[[File:PM.jpg|right|300px|thumb|Figure 4.3.]]
[[File:PM.jpg|right|300px|thumb|Figure 4.3.]]


[[File:Gnaiger 2020 BEC MitoPathways.jpg|left|66px|link=https://www.bioenergetics-communications.org/index.php/Gnaiger_2020_BEC_MitoPathways|Gnaiger 2020 BEC MitoPathways]]
[[File:Gnaiger 2020 BEC MitoPathways.jpg|left|66px|link=https://www.bioenergetics-communications.org/index.php/bec/article/view/gnaiger_2020_mitopathways|Gnaiger 2020 BEC MitoPathways]]
== Chapter 4. NADH-linked pathways through Complex I: respiratory pathway control with pruvate, glutamate, malate ==
== Chapter 4. NADH-linked pathways through Complex I: respiratory pathway control with pruvate, glutamate, malate ==
    
    
=== References: 4. N-pathways ===
=== References: 4. N-pathways ===
:::# Brandt U (2006) Energy converting NADH:quinone oxidoreductase (Complex I). Annu Rev Biochem 75:69-92.
:::# Brandt U (2006) Energy converting NADH:quinone oxidoreductase (Complex I). Annu Rev Biochem 75:69-92.
:::# Brewer GJ, Jones TT, Wallimann T, Schlattner U (2004) Higher respiratory rates and improved creatine stimulation in brain mitochondria isolated with antioxidants. Mitochondrion 4:49-57. - [[Brewer 2004 Mitochondrion |»Bioblast link«]]
:::# Brewer GJ, Jones TT, Wallimann T, Schlattner U (2004) Higher respiratory rates and improved creatine stimulation in brain mitochondria isolated with antioxidants. - [[Brewer 2004 Mitochondrion |»Bioblast link«]]
:::# Chance B, Williams GR (1955) Respiratory enzymes in oxidative phosphorylation. III. The steady state. J Biol Chem 217:409-27. - [[Chance 1955 J Biol Chem-III |»Bioblast link«]] - Substrate depletion in isolated mitochondria is achieved in State 2: ADP is added to induce a transient stimulation of oxygen flux based on oxidation of endogenous substrates.  
:::# Chance B, Williams GR (1955) Respiratory enzymes in oxidative phosphorylation. III. The steady state. - [[Chance 1955 J Biol Chem-III |»Bioblast link«]] - Substrate depletion in isolated mitochondria is achieved in State 2: ADP is added to induce a transient stimulation of oxygen flux based on oxidation of endogenous substrates.  
:::# Digerness SB, Reddy WJ (1976) The malate-aspartate shuttle in heart mitochondria. J Mol Cell Cardiol. 8:779-85.
:::# Digerness SB, Reddy WJ (1976) The malate-aspartate shuttle in heart mitochondria. J Mol Cell Cardiol. 8:779-85.
:::# Duchen MR (2004) Roles of mitochondria in health and disease. Diabetes 53, Suppl 1:S96-102. - Mitochondrial glutamate dehydrogenase is particularly active in astrocytes, preventing glutamate induced neurotoxicity.
:::# Duchen MR (2004) Roles of mitochondria in health and disease. Diabetes 53, Suppl 1:S96-102. - Mitochondrial glutamate dehydrogenase is particularly active in astrocytes, preventing glutamate induced neurotoxicity.
:::# Gnaiger E (2009) Capacity of oxidative phosphorylation in human skeletal muscle. New perspectives of mitochondrial physiology. Int J Biochem Cell Biol 41:1837–45. - [[Gnaiger 2009 Int J Biochem Cell Biol |»Bioblast link«]]
:::# Gnaiger E (2009) Capacity of oxidative phosphorylation in human skeletal muscle. New perspectives of mitochondrial physiology. - [[Gnaiger 2009 Int J Biochem Cell Biol |»Bioblast link«]]
:::# Gnaiger E, Méndez G, Hand SC (2000) High phosphorylation efficiency and depression of uncoupled respiration in mitochondria under hypoxia. Proc Natl Acad Sci U S A 97:11080-5. - [[Gnaiger 2000 Proc Natl Acad Sci U S A |»Bioblast link«]] - Equilibrium ratio of malate to fumarate is 4.1.
:::# Gnaiger E, Méndez G, Hand SC (2000) High phosphorylation efficiency and depression of uncoupled respiration in mitochondria under hypoxia. - [[Gnaiger 2000 Proc Natl Acad Sci U S A |»Bioblast link«]] - Equilibrium ratio of malate to fumarate is 4.1.
:::# Hildyard JCW, Halestrap AP (2003) Identification of the mitochondrial pyruvate carrier in ''Saccharomyces cerevidiae''. Biochem J 374:607-11.
:::# Hildyard JCW, Halestrap AP (2003) Identification of the mitochondrial pyruvate carrier in ''Saccharomyces cerevidiae''. Biochem J 374:607-11.
:::# Johnson G, Roussel D, Dumas JF, Douay O, Malthiery Y, Simard G, Ritz P (2006) Influence of intensity of food restriction on skeletal muscle mitochondrial energy metabolism in rats. Am J Physiol Endocrinol Metab 291:E460-7. - Uncoupling stimulates coupled OXPHOS respiration, PM<sub>''P''</sub>, by 14 %.
:::# Johnson G, Roussel D, Dumas JF, Douay O, Malthiery Y, Simard G, Ritz P (2006) Influence of intensity of food restriction on skeletal muscle mitochondrial energy metabolism in rats. Am J Physiol Endocrinol Metab 291:E460-7. - Uncoupling stimulates coupled OXPHOS respiration, PM<sub>''P''</sub>, by 14 %.
:::# Kemp RB, Hoare S, Schmalfeldt M, Bridge CM, Evans PM, Gnaiger E (1994) A thermochemical study of the production of lactate by glutaminolysis and glycolysis in mouse macrophage hybridoma cells. In What is Controlling Life? (Gnaiger E, Gellerich FN, Wyss M, eds) Modern Trends in BioThermoKinetics 3, Innsbruck Univ Press:226-31. - [[Kemp 1994 BTK-226 |»Bioblast link«]] - Glutamate derived from hydrolyzation of glutamine is a very important aerobic substrate in cultured cells.
:::# Kemp RB, Hoare S, Schmalfeldt M, Bridge CM, Evans PM, Gnaiger E (1994) A thermochemical study of the production of lactate by glutaminolysis and glycolysis in mouse macrophage hybridoma cells. - [[Kemp 1994 BTK-226 |»Bioblast link«]] - Glutamate derived from hydrolyzation of glutamine is a very important aerobic substrate in cultured cells.
:::# Lemasters JJ (1984) The ATP-to-oxygen stoichiometries of oxidative phosphorylation by rat liver mitochondria. J Biol Chem 259:13123-30. - [[Lemasters 1984 J Biol Chem |»Bioblast link«]] - Malonate added to inhibit the succinate-fumarate reaction exerts only a minor effect on liver mitochondrial respiration.
:::# Lemasters JJ (1984) The ATP-to-oxygen stoichiometries of oxidative phosphorylation by rat liver mitochondria. - [[Lemasters 1984 J Biol Chem |»Bioblast link«]] - Malonate added to inhibit the succinate-fumarate reaction exerts only a minor effect on liver mitochondrial respiration.
:::# Maechler P, Carobbio S, Rubi B (2006) In beta-cells, mitochondria integrate and generate metabolic signals controlling insulin secretion. Int J Biochem Cell Biol 38:696-709.
:::# Maechler P, Carobbio S, Rubi B (2006) In beta-cells, mitochondria integrate and generate metabolic signals controlling insulin secretion. Int J Biochem Cell Biol 38:696-709.
:::# Messer JI, Jackman MR, Willis WT (2004) Pyruvate and citric acid cycle carbon requirements in isolated skeletal muscle mitochondria. Am J Physiol Cell Physiol 286:C565-72. - [[Messer 2004 Am J Physiol Cell Physiol |»Bioblast link«]] - With malate alone and saturating [ADP] isolated rat skeletal muscle mitochondria respire at only 1.3 % of OXPHOS capacity with pyruvate+malate. Pyruvate alone yields only 2.1 % of OXPHOS capacity (''P'') with PM.
:::# Messer JI, Jackman MR, Willis WT (2004) Pyruvate and citric acid cycle carbon requirements in isolated skeletal muscle mitochondria. - [[Messer 2004 Am J Physiol Cell Physiol |»Bioblast link«]] - With malate alone and saturating [ADP] isolated rat skeletal muscle mitochondria respire at only 1.3 % of OXPHOS capacity with pyruvate+malate. Pyruvate alone yields only 2.1 % of OXPHOS capacity (''P'') with PM.
:::# Nicholls DG, Ferguson SJ (2002) Bioenergetics 3, Academic Press, London:287 pp. - [[Nicholls 2013 Academic Press |»Bioblast link«]] - Carriers.
:::# Nicholls DG, Ferguson SJ (2002) Bioenergetics 3. - [[Nicholls 2013 Academic Press |»Bioblast link«]] - Carriers.
:::# Ouhabi R, Boue-Grabot M, Mazat J-P (1994) ATP synthesis in permeabilized cells: Assessment of the ATP/O ratios in situ. In What is Controlling Life? (Gnaiger E, Gellerich FN, Wyss M, eds) Modern Trends in BioThermoKinetics 3, Innsbruck Univ Press:141-4. - [[Ouhabi 1994 Modern Trends in BioThermoKinetics 3 |»Bioblast link«]] - In fibroblasts, GM<sub>''P''</sub> supports a higher respiratory flux than PM<sub>''P''</sub>.
:::# Ouhabi R, Boue-Grabot M, Mazat J-P (1994) ATP synthesis in permeabilized cells: Assessment of the ATP/O ratios in situ. - [[Ouhabi 1994 Modern Trends in BioThermoKinetics 3 |»Bioblast link«]] - In fibroblasts, GM<sub>''P''</sub> supports a higher respiratory flux than PM<sub>''P''</sub>.
:::# O’Donnell JM, Kudej RK, LaNoue KF, Vatner SF, Lewandowski ED (2004) Limited transfer of cytosolic NADH into mitochondria at high cardiac workload. Am J Physiol Heart Circ Physiol 286:H2237-42.
:::# O’Donnell JM, Kudej RK, LaNoue KF, Vatner SF, Lewandowski ED (2004) Limited transfer of cytosolic NADH into mitochondria at high cardiac workload. Am J Physiol Heart Circ Physiol 286:H2237-42.
:::# Puchowicz MA, Varnes ME, Cohen BH, Friedman NR, Kerr DS, Hoppel CL (2004) Oxidative phosphorylation analysis: assessing the integrated functional activity of human skeletal muscle mitochondria – case studies. Mitochondrion 4:377-85. - [[Puchowicz 2004 Mitochondrion |»Bioblast link«]] - OXPHOS with glutamate alone is 50 % to 85 % of respiration with glutamate&malate. Accumulation of fumarate inhibits succinate dehydrogenase and glutamate dehydrogenase (Caughey et al 1957; Dervartanian, Veeger 1964). - OXPHOS with glutamate&malate is identical or 10 % higher than with pyruvate&malate.
:::# Puchowicz MA, Varnes ME, Cohen BH, Friedman NR, Kerr DS, Hoppel CL (2004) Oxidative phosphorylation analysis: assessing the integrated functional activity of human skeletal muscle mitochondria – case studies. - [[Puchowicz 2004 Mitochondrion |»Bioblast link«]] - OXPHOS with glutamate alone is 50 % to 85 % of respiration with glutamate&malate. Accumulation of fumarate inhibits succinate dehydrogenase and glutamate dehydrogenase (Caughey et al 1957; Dervartanian, Veeger 1964). - OXPHOS with glutamate&malate is identical or 10 % higher than with pyruvate&malate.
:::# Rasmussen UF, Rasmussen HN (2000) Human quadriceps muscle mitochondria: A functional characterization. Mol Cell Biochem 208:37-44. - [[Rasmussen 2000 Mol Cell Biochem |»Bioblast link«]] - Uncoupling stimulates coupled OXPHOS respiration, PM<sub>''P''</sub>, by 15 % in human skeletal muscle. OXPHOS with glutamate alone is 50 % to 85 % of respiration with glutamate&malate. - OXPHOS with glutamate&malate is identical or 10 % higher than with pyruvate&malate.
:::# Rasmussen UF, Rasmussen HN (2000) Human quadriceps muscle mitochondria: A functional characterization. - [[Rasmussen 2000 Mol Cell Biochem |»Bioblast link«]] - Uncoupling stimulates coupled OXPHOS respiration, PM<sub>''P''</sub>, by 15 % in human skeletal muscle. OXPHOS with glutamate alone is 50 % to 85 % of respiration with glutamate&malate. - OXPHOS with glutamate&malate is identical or 10 % higher than with pyruvate&malate.
:::# Schöpf B, Weissensteiner H, Schäfer G, Fazzini F, Charoentong P, Naschberger A, Rupp B, Fendt L, Bukur V, Giese I, Sorn P, Sant’Anna-Silva AC, Iglesias-Gonzalez J, Sahin U, Kronenberg F, Gnaiger E, Klocker H (2020) OXPHOS remodeling in high-grade prostate cancer involves mtDNA mutations and increased succinate oxidation. Nat Commun 11:1487. - [[Schoepf 2020 Nat Commun |»Bioblast link«]]
:::# Schöpf B, Weissensteiner H, Schäfer G, Fazzini F, Charoentong P, Naschberger A, Rupp B, Fendt L, Bukur V, Giese I, Sorn P, Sant’Anna-Silva AC, Iglesias-Gonzalez J, Sahin U, Kronenberg F, Gnaiger E, Klocker H (2020) OXPHOS remodeling in high-grade prostate cancer involves mtDNA mutations and increased succinate oxidation. - [[Schoepf 2020 Nat Commun |»Bioblast link«]]
:::# Swenson Erik R (2018) Does aerobic respiration produce carbon dioxide or hydrogen ion and bicarbonate? Anesthesiology 128:873–9. - [[Swenson 2018 Anesthesiology |»Bioblast link«]]
:::# Swenson ER (2018) Does aerobic respiration produce carbon dioxide or hydrogen ion and bicarbonate? - [[Swenson 2018 Anesthesiology |»Bioblast link«]]
:::# Thomas et al (2004) - OXPHOS in human skeletal muscle for PM<sub>''P''</sub> is 25 % higher than for GM<sub>''P''</sub>.
:::# Thomas et al (2004) - OXPHOS in human skeletal muscle for PM<sub>''P''</sub> is 25 % higher than for GM<sub>''P''</sub>.
:::# Winkler-Stuck K, Kirches E, Mawrin C, Dietzmann K, Lins H, Wallesch CW, Kunz WS, Wiedemann FR (2005) Re-evaluation of the dysfunction of mitochondrial respiratory chain in skeletal muscle of patients with Parkinson's disease. J Neural Transm 112:499-518. - [[Winkler-Stuck 2005 J Neural Transm |»Bioblast link«]] - OXPHOS in human skeletal muscle for PM<sub>''P''</sub> is 16% higher than for GM<sub>''P''</sub>.
:::# Winkler-Stuck K, Kirches E, Mawrin C, Dietzmann K, Lins H, Wallesch CW, Kunz WS, Wiedemann FR (2005) Re-evaluation of the dysfunction of mitochondrial respiratory chain in skeletal muscle of patients with Parkinson's disease. - [[Winkler-Stuck 2005 J Neural Transm |»Bioblast link«]] - OXPHOS in human skeletal muscle for PM<sub>''P''</sub> is 16% higher than for GM<sub>''P''</sub>.
:::# [[MitoPedia]]
:::# [[MitoPedia]]
::::» [[Malic enzyme]]
::::» [[Malic enzyme]]
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[[File:S(Rot).jpg|right|300px|thumb|Fig. 5.1.]]
[[File:S(Rot).jpg|right|300px|thumb|Figure 5.1.]]
[[File:Gnaiger 2020 BEC MitoPathways.jpg|left|66px|link=https://www.bioenergetics-communications.org/index.php/Gnaiger_2020_BEC_MitoPathways|Gnaiger 2020 BEC MitoPathways]]
[[File:Gnaiger 2020 BEC MitoPathways.jpg|left|66px|link=https://www.bioenergetics-communications.org/index.php/bec/article/view/gnaiger_2020_mitopathways|Gnaiger 2020 BEC MitoPathways]]
== Chapter 5. S-pathway through Complex II, F-pathway through electron-transferring flavoprotein, Gp-pathway through glycerophosphate dehydrogenase ==
== Chapter 5. S-pathway through Complex II, F-pathway through electron-transferring flavoprotein, Gp-pathway through glycerophosphate dehydrogenase ==


Line 230: Line 233:
:::# Jackman MR, Willis WT (1996) Characteristics of mitochondria isolated from type I and type IIb skeletal muscle. Am J Physiol Cell Physiol 270:C673-8. - Glycerophosphate oxidation is 10-fold higher in rabbit gracilis mitochondria compared to soleus.
:::# Jackman MR, Willis WT (1996) Characteristics of mitochondria isolated from type I and type IIb skeletal muscle. Am J Physiol Cell Physiol 270:C673-8. - Glycerophosphate oxidation is 10-fold higher in rabbit gracilis mitochondria compared to soleus.
:::# Lehninger AL (1970) Biochemistry. The molecular basis of cell structure and function Worth:833 pp. - Oxaloacetate is a more potent competitive inhibitor of succinate dehydrogenase than malonate even at small concentration (p 352).
:::# Lehninger AL (1970) Biochemistry. The molecular basis of cell structure and function Worth:833 pp. - Oxaloacetate is a more potent competitive inhibitor of succinate dehydrogenase than malonate even at small concentration (p 352).
:::# Muller FL, Liu Y, Abdul-Ghani MA, Lustgarten MS, Bhattacharya A, Jang YC, Van Remmen H (2008) High rates of superoxide production in skeletal-muscle mitochondria respiring on both Complex I- and Complex II-linked substrates. Biochem J 409:491–9. - [[Muller 2008 Biochem J |»Bioblast link«]] - Addition of malate inhibits superoxide production with succinate, probably due to the oxaloacetate inhibition of CII.
:::# Muller FL, Liu Y, Abdul-Ghani MA, Lustgarten MS, Bhattacharya A, Jang YC, Van Remmen H (2008) High rates of superoxide production in skeletal-muscle mitochondria respiring on both Complex I- and Complex II-linked substrates. - [[Muller 2008 Biochem J |»Bioblast link«]] - Addition of malate inhibits superoxide production with succinate, probably due to the oxaloacetate inhibition of CII.
:::# Rasmussen UF, Rasmussen HN (2000) Human quadriceps muscle mitochondria: A functional characterization. Mol Cell Biochem 208:37-44. - [[Rasmussen 2000 Mol Cell Biochem |»Bioblast link«]] – Glycerophosphate oxidation is relatively slow.
:::# Rasmussen UF, Rasmussen HN (2000) Human quadriceps muscle mitochondria: A functional characterization. - [[Rasmussen 2000 Mol Cell Biochem |»Bioblast link«]] – Glycerophosphate oxidation is relatively slow.
:::# Rauchova H, Drahota Z, Rauch P, Fato R, Lenaz G (2003) Coenzyme Q releases the inhibitory effect of free fatty acids on mitochondrial glycerophosphate dehydrogenase. Acta Biochim Polonica 50:405-13. - Glycerophosphate is an important substrate for respiration in brown adipose tissue mitochondria.
:::# Rauchova H, Drahota Z, Rauch P, Fato R, Lenaz G (2003) Coenzyme Q releases the inhibitory effect of free fatty acids on mitochondrial glycerophosphate dehydrogenase. Acta Biochim Polonica 50:405-13. - Glycerophosphate is an important substrate for respiration in brown adipose tissue mitochondria.
:::# Sun F, Huo X, Zhai Y, Wang A, Xu J, Su D, Bartlam M, Rao Z (2005) Crystal structure of mitochondrial respiratory membrane protein Complex II. Cell 121:1043–57.
:::# Sun F, Huo X, Zhai Y, Wang A, Xu J, Su D, Bartlam M, Rao Z (2005) Crystal structure of mitochondrial respiratory membrane protein Complex II. Cell 121:1043–57.
Line 243: Line 246:
:::# Ponsot et al (2005) J Cell Physiol 203:479-86. - ‘.. the mitochondrial form of GPDH, which produces FADH2 within the mitochondrial matrix and provides electrons to Compoex II of the phosphorylation chain’. – The mitochondrial glycerophosphate dehydrogenase complex (CGpDH), located on the outer side of the inner mitochondrial membrane, does not provide electrons to CII, but feeds electrons into the Q-cycle entirely independent of CII. FADH<sub>2</sub> is not produced within the mitochondrial matrix. Electron transfer takes place from the mitochondrial inner membrane flavoprotein-linked glycerophosphate dehydrogenase complex to CoQ.
:::# Ponsot et al (2005) J Cell Physiol 203:479-86. - ‘.. the mitochondrial form of GPDH, which produces FADH2 within the mitochondrial matrix and provides electrons to Compoex II of the phosphorylation chain’. – The mitochondrial glycerophosphate dehydrogenase complex (CGpDH), located on the outer side of the inner mitochondrial membrane, does not provide electrons to CII, but feeds electrons into the Q-cycle entirely independent of CII. FADH<sub>2</sub> is not produced within the mitochondrial matrix. Electron transfer takes place from the mitochondrial inner membrane flavoprotein-linked glycerophosphate dehydrogenase complex to CoQ.
   
   
[[File:Gnaiger 2020 BEC MitoPathways.jpg|left|66px|link=https://www.bioenergetics-communications.org/index.php/Gnaiger_2020_BEC_MitoPathways|Gnaiger 2020 BEC MitoPathways]]
[[File:Gnaiger 2020 BEC MitoPathways.jpg|left|66px|link=https://www.bioenergetics-communications.org/index.php/bec/article/view/gnaiger_2020_mitopathways|Gnaiger 2020 BEC MitoPathways]]
[[File:OXPHOS_pathways.jpg|right|500px|thumb|Fig. 5.4.]]
[[File:OXPHOS_pathways.jpg|right|500px|thumb|Figure 6.3.]]
== Chapter 6. NS-pathway through Complexes CI & CII: convergent electron transfer at the Q-junction and additive effect of substrate combinations ==
== Chapter 6. NS-pathway through Complexes CI & CII: convergent electron transfer at the Q-junction and additive effect of substrate combinations ==


=== References: 6. Q-junction ===
=== References: 6. Q-junction ===
:::# Aragonés J, Schneider M, Van Geyte K, Fraisl P, Dresselaers T, Mazzone M, Dirkx R, Zacchigna S, Lemieux H, Jeoung NH, Lambrechts D, Bishop T, Lafuste P, Diez-Juan A, K Harten S, Van Noten P, De Bock K, Willam C, Tjwa M, Grosfeld A, Navet R, Moons L, Vandendriessche T, Deroose C, Wijeyekoon B, Nuyts J, Jordan B, Silasi-Mansat R, Lupu F, Dewerchin M, Pugh C, Salmon P, Mortelmans L, Gallez B, Gorus F, Buyse J, Sluse F, Harris RA, Gnaiger E, Hespel P, Van Hecke P, Schuit F, Van Veldhoven P, Ratcliffe P, Baes M, Maxwell P, Carmeliet P (2008) Deficiency or inhibition of oxygen sensor Phd1 induces hypoxia tolerance by reprogramming basal metabolism. Nat Genet 40:170-80. - [[Aragones 2008 Nat Genet |»Bioblast link«]] - OXPHOS analysis for phenotyping.
:::# Aragonés J, Schneider M, Van Geyte K, Fraisl P, Dresselaers T, Mazzone M, Dirkx R, Zacchigna S, Lemieux H, Jeoung NH, Lambrechts D, Bishop T, Lafuste P, Diez-Juan A, K Harten S, Van Noten P, De Bock K, Willam C, Tjwa M, Grosfeld A, Navet R, Moons L, Vandendriessche T, Deroose C, Wijeyekoon B, Nuyts J, Jordan B, Silasi-Mansat R, Lupu F, Dewerchin M, Pugh C, Salmon P, Mortelmans L, Gallez B, Gorus F, Buyse J, Sluse F, Harris RA, Gnaiger E, Hespel P, Van Hecke P, Schuit F, Van Veldhoven P, Ratcliffe P, Baes M, Maxwell P, Carmeliet P (2008) Deficiency or inhibition of oxygen sensor Phd1 induces hypoxia tolerance by reprogramming basal metabolism. - [[Aragones 2008 Nat Genet |»Bioblast link«]] - OXPHOS analysis for phenotyping.
:::# Bianchi C, Genova ML, Parenti Castelli G, Lenaz G (2004) The mitochondrial respiratory chain is partially organized in a supercomplex assembly: kinetic evidence using flux control analysis. J Biol Chem 279:36562-9. - [[Bianchi 2004 J Biol Chem |»Bioblast link«]]
:::# Bianchi C, Genova ML, Parenti Castelli G, Lenaz G (2004) The mitochondrial respiratory chain is partially organized in a supercomplex assembly: kinetic evidence using flux control analysis. - [[Bianchi 2004 J Biol Chem |»Bioblast link«]]
:::# Boushel R, Gnaiger E, Calbet JA, Gonzalez-Alonso J, Wright-Paradis C, Sondergaard H, Ara I, Helge JW, Saltin B (2011) Muscle mitochondrial capacity exceeds maximal oxygen delivery in humans. Mitochondrion 11:303-7. - [[Boushel 2011 Mitochondrion |»Bioblast link«]]
:::# Boushel R, Gnaiger E, Calbet JA, Gonzalez-Alonso J, Wright-Paradis C, Sondergaard H, Ara I, Helge JW, Saltin B (2011) Muscle mitochondrial capacity exceeds maximal oxygen delivery in humans. - [[Boushel 2011 Mitochondrion |»Bioblast link«]]
:::# Boushel R, Gnaiger E, Schjerling P, Skovbro M, Kraunsoe R, Flemming D (2007) Patients with Type 2 Diabetes have normal mitochondrial function in skeletal muscle. Diabetologia 50:790-6. - [[Boushel 2007 Diabetologia |»Bioblast link«]]
:::# Boushel R, Gnaiger E, Schjerling P, Skovbro M, Kraunsoe R, Flemming D (2007) Patients with Type 2 Diabetes have normal mitochondrial function in skeletal muscle. - [[Boushel 2007 Diabetologia |»Bioblast link«]]
:::# Capel F, Rimbert V, Lioger D, Diot A, Rousset P, Patureau Mirand P, Boirie Y, Morio B, Mosoni L (2005) Due to reverse electron transfer, mitochondrial H2O2 release increases with age in human vastus lateralis muscle although oxidative capacity is preserved. Mech Ageing Develop 126:505-11. - CI<small>&</small>II substrate combination.
:::# Capel F, Rimbert V, Lioger D, Diot A, Rousset P, Patureau Mirand P, Boirie Y, Morio B, Mosoni L (2005) Due to reverse electron transfer, mitochondrial H2O2 release increases with age in human vastus lateralis muscle although oxidative capacity is preserved. Mech Ageing Develop 126:505-11. - NS-substrate combination.
:::# Chance B (1965) Reaction of oxygen with the respiratory chain in cells and tissues. J Gen Physiol 49:163-88. - Glutamate&succinate as respiratory substrate combination, without comparison of flux with different substrates.
:::# Chance B (1965) Reaction of oxygen with the respiratory chain in cells and tissues. J Gen Physiol 49:163-88. - Glutamate&succinate as respiratory substrate combination, without comparison of flux with different substrates.
:::# Costa LE, Boveris A, Koch OR, Taquini AC (1988) Liver and heart mitochondria in rats submitted to chronic hypobaric hypoxia. Am J Physiol Cell Physiol 255:C123-C9.
:::# Costa LE, Boveris A, Koch OR, Taquini AC (1988) Liver and heart mitochondria in rats submitted to chronic hypobaric hypoxia. Am J Physiol Cell Physiol 255:C123-C9.
:::# Digerness SB, Reddy WJ (1976) The malate-aspartate shuttle in heart mitochondria. J Mol Cell Cardiol. 8:779-85.
:::# Digerness SB, Reddy WJ (1976) The malate-aspartate shuttle in heart mitochondria. J Mol Cell Cardiol. 8:779-85.
:::# Eberhart K, Rainer J, Bindreither D, Ritter I, Gnaiger E, Kofler R, Oefner PJ, Renner K (2011) Glucocorticoid-induced alterations in mitochondrial membrane properties and respiration in childhood acute lymphoblastic leukemia. Biochim Biophys Acta 1807:719-25. - [[Eberhart 2011 Biochim Biophys Acta |»Bioblast link«]]
:::# Eberhart K, Rainer J, Bindreither D, Ritter I, Gnaiger E, Kofler R, Oefner PJ, Renner K (2011) Glucocorticoid-induced alterations in mitochondrial membrane properties and respiration in childhood acute lymphoblastic leukemia. - [[Eberhart 2011 Biochim Biophys Acta |»Bioblast link«]]
:::# Estabrook R (1967) Mitochondrial respiratory control and the polarographic measurement of ADP:O ratios. Meth Enzymol 10:41-7. - [[Estabrook 1967 Methods Enzymol |»Bioblast link«]]
:::# Estabrook R (1967) Mitochondrial respiratory control and the polarographic measurement of ADP:O ratios. - [[Estabrook 1967 Methods Enzymol |»Bioblast link«]]
:::# Garait B, Couturier K, Servais S, Letexier D, Perrin D, Batandier C, Rouanet J-L, Sibille B, Rey B, Leverve X, Favier R (2005) Fat intake reverses the beneficial effects of low caloric intake on skeletal muscle mitochondrial H2O2 production. Free Radic Biol Med 39:1249–61. - GM<sub>''P''</sub>/GMS<sub>''P''</sub> substrate control ratio in skeletal muscle of rats fed on various diets ranges from 0.7 to 0.8.  
:::# Garait B, Couturier K, Servais S, Letexier D, Perrin D, Batandier C, Rouanet J-L, Sibille B, Rey B, Leverve X, Favier R (2005) Fat intake reverses the beneficial effects of low caloric intake on skeletal muscle mitochondrial H2O2 production. Free Radic Biol Med 39:1249–61. - GM<sub>''P''</sub>/GMS<sub>''P''</sub> substrate control ratio in skeletal muscle of rats fed on various diets ranges from 0.7 to 0.8.  
:::# Gnaiger E (2009) Capacity of oxidative phosphorylation in human skeletal muscle. New perspectives of mitochondrial physiology. Int J Biochem Cell Biol 41:1837–45. - [[Gnaiger 2009 Int J Biochem Cell Biol |»Bioblast link«]]
:::# Gnaiger E (2009) Capacity of oxidative phosphorylation in human skeletal muscle. New perspectives of mitochondrial physiology. - [[Gnaiger 2009 Int J Biochem Cell Biol |»Bioblast link«]]
:::# Gnaiger E, Boushel R, Søndergaard H, Munch-Andersen T, Damsgaard R, Hagen C, Díez-Sánchez C, Ara I, Wright-Paradis C, Schrauwen P, Hesselink M, Calbet JAL, Christiansen M, Helge JW, Saltin B (2015) Mitochondrial coupling and capacity of oxidative phosphorylation in skeletal muscle of Inuit and caucasians in the arctic winter. Scand J Med Sci Sports 25 (Suppl 4):126–34. - [[Gnaiger 2015 Scand J Med Sci Sports |»Bioblast link«]]
:::# Gnaiger E, Boushel R, Søndergaard H, Munch-Andersen T, Damsgaard R, Hagen C, Díez-Sánchez C, Ara I, Wright-Paradis C, Schrauwen P, Hesselink M, Calbet JAL, Christiansen M, Helge JW, Saltin B (2015) Mitochondrial coupling and capacity of oxidative phosphorylation in skeletal muscle of Inuit and caucasians in the arctic winter. - [[Gnaiger 2015 Scand J Med Sci Sports |»Bioblast link«]]
:::# Gnaiger E, Wright-Paradis C, Sondergaard H, Lundby C, Calbet JA, Saltin B, Helge J, Boushel R (2005) High-resolution respirometry in small biopsies of human muscle: correlations with body mass index and age. Mitochondr Physiol Network 10.9:14-5. - [[Gnaiger 2005 Abstract MiP2005 |»Bioblast link«]]
:::# Gnaiger E, Wright-Paradis C, Sondergaard H, Lundby C, Calbet JA, Saltin B, Helge J, Boushel R (2005) High-resolution respirometry in small biopsies of human muscle: correlations with body mass index and age. - [[Gnaiger 2005 Abstract MiP2005 |»Bioblast link«]]
:::# González-Flecha B, Cutrin JC, Boveris A (1993) Time course and mechanism of oxidative stress and tissue damage in rat liver subjected to in vivo ischemia-reperfusion. J Clin Invest 91:456-64. - Respiration was measured in states GS<sub>''P''</sub> and GM<sub>''P''</sub>.
:::# González-Flecha B, Cutrin JC, Boveris A (1993) Time course and mechanism of oxidative stress and tissue damage in rat liver subjected to in vivo ischemia-reperfusion. J Clin Invest 91:456-64. - Respiration was measured in states GS<sub>''P''</sub> and GM<sub>''P''</sub>.
:::# Gutman M, Coles CJ, Singer TP, Casida JE (1971) On the functional organization of the respiratory chain at the dehydrogenase-coenzyme Q junction. Biochemistry 10:2036-43.
:::# Gutman M, Coles CJ, Singer TP, Casida JE (1971) On the functional organization of the respiratory chain at the dehydrogenase-coenzyme Q junction. Biochemistry 10:2036-43.
:::# Hansford RG, Hogue BA, Mildaziene V (1997) Dependence of H2O2 formation by rat heart mitochondria on substrate availability and donor age. J Bioenerg Biomembr 29:89–95.
:::# Hansford RG, Hogue BA, Mildaziene V (1997) Dependence of H<sub>2</sub>O<sub>2</sub> formation by rat heart mitochondria on substrate availability and donor age. J Bioenerg Biomembr 29:89–95.
:::# Hatefi Y, Haavik AG, Fowler LR, Griffiths DE (1962) Studies on the electron transfer-pathway. XLII. Reconstitution of the electron transfer-pathway. J Biol Chem 237:2661-9. - [[Hatefi 1962 J Biol Chem-XLII |»Bioblast link«]]
:::# Hatefi Y, Haavik AG, Fowler LR, Griffiths DE (1962) Studies on the electron transfer-pathway. XLII. Reconstitution of the electron transfer-pathway. - [[Hatefi 1962 J Biol Chem-XLII |»Bioblast link«]]
:::# König T, Nicholls DG, Garland PB (1969) The inhibition of pyruvate and Ls(+)-isocitrate oxidation by succinate oxidation in rat liver mitochondria. Biochem J 114:589-96. - [[Koenig 1969 Biochem J |»Bioblast link«]]
:::# König T, Nicholls DG, Garland PB (1969) The inhibition of pyruvate and Ls(+)-isocitrate oxidation by succinate oxidation in rat liver mitochondria. - [[Koenig 1969 Biochem J |»Bioblast link«]]
:::# Krebs HA (1935) CXCVII. Metabolism of amino-acids. III. Deamination of amino-acids. Biochem J 29:1620-44.
:::# Krebs HA (1935) CXCVII. Metabolism of amino-acids. III. Deamination of amino-acids. Biochem J 29:1620-44.
:::# Kunz WS, Kudin A, Vielhaber S, Elger CE, Attardi G, Villani G (2000) Flux control of cytochrome c oxidase in human skeletal muscle. J Biol Chem 275:27741-5. - [[Kunz 2000 J Biol Chem |»Bioblast link«]]
:::# Kunz WS, Kudin A, Vielhaber S, Elger CE, Attardi G, Villani G (2000) Flux control of cytochrome c oxidase in human skeletal muscle. - [[Kunz 2000 J Biol Chem |»Bioblast link«]]
:::# Kuznetsov AV, Clark JF, Winkler K, Kunz WS (1996) Increase of flux control of cytochrome c oxidase in copper-deficient mottled brindled mice. J Biol Chem 271:283-8. - [[Kuznetsov 1996 J Biol Chem |»Bioblast link«]]
:::# Kuznetsov AV, Clark JF, Winkler K, Kunz WS (1996) Increase of flux control of cytochrome c oxidase in copper-deficient mottled brindled mice. - [[Kuznetsov 1996 J Biol Chem |»Bioblast link«]]
:::# Kuznetsov AV, Strobl D, Ruttmann E, Königsrainer A, Margreiter R, Gnaiger E (2002) Evaluation of mitochondrial respiratory function in small biopsies of liver. Analyt Biochem 305:186-94. - [[Kuznetsov 2002 Anal Biochem |»Bioblast link«]] - S(Rot) alone supports a higher flux than GM in liver mitocondria.
:::# Kuznetsov AV, Strobl D, Ruttmann E, Königsrainer A, Margreiter R, Gnaiger E (2002) Evaluation of mitochondrial respiratory function in small biopsies of liver. - [[Kuznetsov 2002 Anal Biochem |»Bioblast link«]] - S(Rot) alone supports a higher flux than GM in liver mitocondria.
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[[File:Gnaiger 2020 BEC MitoPathways.jpg|left|66px|link=https://www.bioenergetics-communications.org/index.php/Gnaiger_2020_BEC_MitoPathways|Gnaiger 2020 BEC MitoPathways]]
[[File:Gnaiger 2020 BEC MitoPathways.jpg|left|66px|link=https://www.bioenergetics-communications.org/index.php/bec/article/view/gnaiger_2020_mitopathways|Gnaiger 2020 BEC MitoPathways]]
== Chapter 7. Additivity of convergent electron transfer ==
== Chapter 7. Additivity of convergent electron transfer ==
    
    
=== References: 7. Additivity ===
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[[File:Gnaiger 2020 BEC MitoPathways.jpg|left|66px|link=https://www.bioenergetics-communications.org/index.php/Gnaiger_2020_BEC_MitoPathways|Gnaiger 2020 BEC MitoPathways]]
[[File:Gnaiger 2020 BEC MitoPathways.jpg|left|66px|link=Gnaiger_2020_BEC_MitoPathways|Gnaiger 2020 BEC MitoPathways]]
[[File:Vector flux and velocity.jpg|right|466px |Vector flux and velocity]]
[[File:Vector flux and velocity.jpg|right|466px |Vector flux and velocity]]
== Chapter 8. Protonmotive pressure and respiratory control ==
== Chapter 8. Protonmotive pressure and respiratory control ==
::::::» [[BEC tutorial-Living Communications: pmF to pmP |'''BEC tutorial-Living Communications: ''pmF'' to ''pmP''''']]


=== References: 8. Protonmotive pressure ===
=== References: 8. Protonmotive pressure ===
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:::# Laner V, Gnaiger E, eds (2014) Mitochondrial physiology – methods, concepts and biomedical perspectives. MiP2014. - [[Laner 2014 Mitochondr Physiol Network MiP2014 |»Bioblast link«]] - ''Mitchell's dream'' by Odra Noel [http://odranoel.eu/category/mitochondrial-art]
:::# Maxwell JC ( 1867) On the dynamical theory of gases. Phil Trans Royal Soc London 157:49-88. - [[Maxwell 1867 Phil Trans Royal Soc London |»Bioblast link«]]
:::# Maxwell JC (1867) On the dynamical theory of gases. - [[Maxwell 1867 Phil Trans Royal Soc London |»Bioblast link«]]
:::# Mitchell P (1961) Coupling of phosphorylation to electron and hydrogen transfer by a chemiosmotic type of mechanism. Nature 191:144-8. - [[Mitchell 1961 Nature |»Bioblast link«]] – Photo: [www.nobelprize.org/nobel_prizes/chemistry/laureates/1978/]  
:::# Mitchell P (1961) Coupling of phosphorylation to electron and hydrogen transfer by a chemiosmotic type of mechanism. - [[Mitchell 1961 Nature |»Bioblast link«]] – Photo: [www.nobelprize.org/nobel_prizes/chemistry/laureates/1978/]  
:::# Mitchell P (1966) Chemiosmotic coupling in oxidative and photosynthetic phosphorylation. Biochim Biophys Acta Bioenergetics 1807 (2011):1507-38. - [[Mitchell 2011 Biochim Biophys Acta |»Bioblast link«]] – ''The Grey Book''
:::# Mitchell P (1966) Chemiosmotic coupling in oxidative and photosynthetic phosphorylation. - [[Mitchell 2011 Biochim Biophys Acta |»Bioblast link«]] – ''The Grey Book''
:::# Mitchell P (1967) Proton current flow in mitochondrial systems. Nature 214:1327–8. - [[Mitchell 1967 Nature |»Bioblast link«]] - A discussion on the small number of protons in a mitochondrion, with emphasis on the membrane potential as the major component of the protonmotive force (p.m.f.).
:::# Mitchell P (1967) Proton current flow in mitochondrial systems. - [[Mitchell 1967 Nature |»Bioblast link«]] - A discussion on the small number of protons in a mitochondrion, with emphasis on the membrane potential as the major component of the protonmotive force (p.m.f.).
:::# Mitchell P, Moyle J (1967) Respiration-driven proton translocation in rat liver mitochondria. Biochem J 105:1147-62. - [[Mitchell 1967 Biochem J |»Bioblast link«]]
:::# Mitchell P, Moyle J (1967) Respiration-driven proton translocation in rat liver mitochondria. - [[Mitchell 1967 Biochem J |»Bioblast link«]]
:::# Mohr PJ, Phillips WD (2015) Dimensionless units in the SI. Metrologia 52:40-7. - [[Mohr 2015 Metrologia |»Bioblast link«]]
:::# Mohr PJ, Phillips WD (2015) Dimensionless units in the SI. - [[Mohr 2015 Metrologia |»Bioblast link«]]
:::# Nernst W (1921) Studies in chemical thermodynamics. Nobel Lecture December 12, 1921. - [[Nernst 1921 Nobel Lecture |»Bioblast link«]]
:::# Nernst W (1921) Studies in chemical thermodynamics. Nobel Lecture December 12, 1921. - [[Nernst 1921 Nobel Lecture |»Bioblast link«]]
:::# Nicholls DG, Ferguson SJ (2013) Bioenergetics4. Academic Press 419 pp. - [[Nicholls 2013 Academic Press |»Bioblast link«]]
:::# Nicholls DG, Ferguson SJ (2013) Bioenergetics4. Academic Press. - [[Nicholls 2013 Academic Press |»Bioblast link«]]
:::# Odra Noel, Gnaiger Erich (2014) MiPArt - Mitchell's dream - Mitchell's equation. MiPNet 19.13:6-8. - [[Odra Noel 2014 MiPNet |»Bioblast link«]]  
:::# Odra Noel, Gnaiger Erich (2014) MiPArt - Mitchell's dream - Mitchell's equation. - [[Odra Noel 2014 MiPNet |»Bioblast link«]]  
:::# Onsager L (1931) Reciprocal relations in irreversible processes. I. Phys Rev 37:405-26. - [[Onsager 1931 Phys Rev |»Bioblast link«]]
:::# Onsager L (1931) Reciprocal relations in irreversible processes. I. - [[Onsager 1931 Phys Rev |»Bioblast link«]]
:::# Patzek Tad W (2014) Fick’s diffusion experiments revisited —Part I. Advances in historical studies 3:194-206. - [[Patzek 2014 Advances in Historical Studies |»Bioblast link«]]
:::# Patzek Tad W (2014) Fick’s diffusion experiments revisited — Part I. - [[Patzek 2014 Advances in Historical Studies |»Bioblast link«]]
:::# Poburko Damon, Santo-Domingo Jaime, Demaurex Nicolas (2011) Dynamic regulation of the mitochondrial proton gradient during cytosolic calcium elevations. J Biol Chem 286:11672-84. - [[Poburko 2011 J Biol Chem |»Bioblast link«]]
:::# Poburko Damon, Santo-Domingo Jaime, Demaurex Nicolas (2011) Dynamic regulation of the mitochondrial proton gradient during cytosolic calcium elevations. - [[Poburko 2011 J Biol Chem |»Bioblast link«]]
:::# Prebble J, Weber B (2003) Wandering in the gardens of the mind. Peter Mitchell and the making of Glynn. Oxford Univ Press.
:::# Prebble J, Weber B (2003) Wandering in the gardens of the mind. Peter Mitchell and the making of Glynn. Oxford Univ Press.
:::# Prigogine I (1967) Introduction to thermodynamics of irreversible processes. Interscience, New York, 3rd ed:147pp. - [[Prigogine 1967 Interscience |»Bioblast link«]]
:::# Prigogine I (1967) Introduction to thermodynamics of irreversible processes. Interscience, New York, 3rd ed. - [[Prigogine 1967 Interscience |»Bioblast link«]]
:::# Rich P (2003) Chemiosmotic coupling: The cost of living. Nature 421:583. - [[Rich 2003 Nature |»Bioblast link«]]
:::# Rich P (2003) Chemiosmotic coupling: The cost of living. - [[Rich 2003 Nature |»Bioblast link«]]
:::# Rottenberg H (1984) Membrane potential and surface potential in mitochondria: uptake and binding of lipophilic cations. J Membr Biol 81:127-38. - [[Rottenberg 1984 J Membr Biol |»Bioblast link«]]
:::# Rottenberg H (1984) Membrane potential and surface potential in mitochondria: uptake and binding of lipophilic cations. - [[Rottenberg 1984 J Membr Biol |»Bioblast link«]]
:::# Scaduto RC Jr, Grotyohann LW (1999) Measurement of mitochondrial membrane potential using fluorescent rhodamine derivatives. Biophys J 76:469-77. - [[Scaduto 1999 Biophys J |»Bioblast link«]]
:::# Scaduto RC Jr, Grotyohann LW (1999) Measurement of mitochondrial membrane potential using fluorescent rhodamine derivatives. - [[Scaduto 1999 Biophys J |»Bioblast link«]]
:::# Schrödinger E (1944) What is life? The physical aspect of the living cell. Cambridge Univ Press. - [[Schrödinger 1944 Cambridge Univ Press |»Bioblast link«]]
:::# Schrödinger E (1944) What is life? The physical aspect of the living cell. Cambridge Univ Press. - [[Schrödinger 1944 Cambridge Univ Press |»Bioblast link«]]
:::# Schwerzmann K, Cruz-Orive LM, Eggman R, Sänger A, Weibel ER (1986) Molecular architecture of the inner membrane of mitochondria from rat liver: a combined biochemical and stereological study. J Cell Biol 102:97-103. - [[Schwerzmann 1986 J Cell Biol |»Bioblast link«]]
:::# Schwerzmann K, Cruz-Orive LM, Eggman R, Sänger A, Weibel ER (1986) Molecular architecture of the inner membrane of mitochondria from rat liver: a combined biochemical and stereological study. - [[Schwerzmann 1986 J Cell Biol |»Bioblast link«]]
:::# Swenson Erik R (2018) Does aerobic respiration produce carbon dioxide or hydrogen ion and bicarbonate? Anesthesiology 128:873–9. - [[Swenson 2018 Anesthesiology |»Bioblast link«]] - Facilitated diffusion: codiffusion with CO<sub>2</sub> of bicarbonate and facilitated H<sup>+</sup> transport by intracellular diffusion of buffer molecules.
:::# Swenson Erik R (2018) Does aerobic respiration produce carbon dioxide or hydrogen ion and bicarbonate? - [[Swenson 2018 Anesthesiology |»Bioblast link«]] - Facilitated diffusion: codiffusion with CO<sub>2</sub> of bicarbonate and facilitated H<sup>+</sup> transport by intracellular diffusion of buffer molecules.
:::# van't Hoff JH (1901) Osmotic pressure and chemical equilibrium. Nobel Lecture December 13, 1901. - [[Van't Hoff 1901 Nobel Lecture |»Bioblast link«]]
:::# van't Hoff JH (1901) Osmotic pressure and chemical equilibrium. Nobel Lecture December 13, 1901. - [[Van't Hoff 1901 Nobel Lecture |»Bioblast link«]]
:::# Wang T (2010) Coulomb force as an entropic force. Phys Rev D 81:104045. - [[Wang 2010 Phys Rev D |»Bioblast link«]]
:::# Wang T (2010) Coulomb force as an entropic force. - [[Wang 2010 Phys Rev D |»Bioblast link«]]
:::# White M (1997) Isaak Newton. The last sorcerer. Fourth Estate, London 402 pp. - [[White 1997 Fourth Estate |»Bioblast link«]]
:::# White M (1997) Isaak Newton. The last sorcerer. Fourth Estate. - [[White 1997 Fourth Estate |»Bioblast link«]]




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== A. Conversions of metabolic fluxes ==
== A. Conversions of metabolic fluxes ==
    
    
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:::# Brooks GA, Hittelman KJ, Faulkner JA, Beyer RE (1971) Temperature, skeletal muscle mitochondrial functions, and oxygen debt. Am J Physiol 220:1053-9.
:::# Brooks GA, Hittelman KJ, Faulkner JA, Beyer RE (1971) Temperature, skeletal muscle mitochondrial functions, and oxygen debt. Am J Physiol 220:1053-9.
:::# Gnaiger E (1983) Symbols and units: Toward standardization. In: Polarographic Oxygen Sensors. Aquatic and Physiological Applications. Gnaiger E, Forstner H (eds), Springer, Berlin, Heidelberg, New York:352-8.
:::# Gnaiger E (1983) Symbols and units: Toward standardization. In: Polarographic Oxygen Sensors. Aquatic and Physiological Applications. Gnaiger E, Forstner H (eds), Springer, Berlin, Heidelberg, New York:352-8.
:::# Lemieux H, Blier PU, Gnaiger E (2017) Remodeling pathway control of mitochondrial respiratory capacity by temperature in mouse heart: electron flow through the Q-junction in permeabilized fibers. Sci Rep 7:2840. - [[Lemieux 2017 Sci Rep |»Bioblast link«]]
:::# Lemieux H, Blier PU, Gnaiger E (2017) Remodeling pathway control of mitochondrial respiratory capacity by temperature in mouse heart: electron flow through the Q-junction in permeabilized fibers. - [[Lemieux 2017 Sci Rep |»Bioblast link«]]
:::# Slater EC, Rosing J, Mol A (1973) The phosphorylation potential generated by respiring mitochondria. Biochim Biophys Acta 292:534-53.
:::# Slater EC, Rosing J, Mol A (1973) The phosphorylation potential generated by respiring mitochondria. Biochim Biophys Acta 292:534-53.


   
   
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== B: SUIT ==
== B: SUIT ==
    
    
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::::» [[MitoPedia: Inhibitors]]
::::» [[MitoPedia: Inhibitors]]


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== Abbreviations ==
== Abbreviations ==


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:::: ETS - electron transfer system
:::: ETS - electron transfer system
:::: ''I''<sub>O<sub>2</sub></sub> - oxygen flow
:::: ''I''<sub>O<sub>2</sub></sub> - oxygen flow
:::: ''j''<sub>cyt ''c''</sub> - cytochrome ''c'' control efficiency; ''j''<sub>cyt ''c''</sub> = (''J''<sub>CHNO''c''</sub>-''J''<sub>CHNO</sub>)/''J''<sub>CHNO''c''</sub> 
:::: ''J''<sub>O<sub>2</sub></sub> - oxygen flux
:::: ''J''<sub>O<sub>2</sub></sub> - oxygen flux
:::: ''j''<sub>''E-L''</sub>=(''E''-''L'')/''E'' - ET-coupling efficiency
:::: ''j''<sub>''E-L''</sub>=(''E''-''L'')/''E'' - ET-coupling efficiency
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== Cited by ==
== Cited by ==
{{Template:Cited by Gnaiger 2020 BEC MitoPhysiology}}
{{Template:Cited by Lane 2022 Transformer}}
:::::: Under 'Further reading': Erich Gnaiger, ''Mitochondrial Pathways and Respiratory Control. An Introduction to OXPHOS Analysis'' (Innsbruck, Bioenergetics Communications, 2020). Available here: http://doi:10.26124/bec:2020-0002. The 'bible' of fluorespirometry, privately published by Erich Gnaiger in the tradition of Peter Mitchell's 'little grey books'; this is the little blue book. Gives practical insights into how the Krebs cycle really works. Introduces the idea of the Q junction, where electrons funnel from many substrates, including glycerol phosphate outside the mitochondria, into complex III.
::::* Gnaiger E, Cardoso LHD, Tindle-Solomon L, Cocco P, eds (2022) Bioblast 2022: BEC inaugural conference. https://doi.org/10.26124/bec:2022-0001
::::* Heimler SR, Phang HJ, Bergstrom J, Mahapatra G, Dozier S, Gnaiger E, Molina AJA (2021) Platelet bioenergetics are associated with resting metabolic rate and exercise capacity in older adult women. https://doi.org/10.26124/bec:2022-0002
::::* Zdrazilova L, Hansikova H, Gnaiger E (2022) Comparable respiratory activity in attached and suspended human fibroblasts. https://doi.org/10.1371/journal.pone.0264496
{{Template:Cited by Komlodi 2022 MitoFit pmF}}
::::* Donnelly C, Schmitt S, Cecatto C, Cardoso LHD, Komlodi T, Place N, Kayser B, Gnaiger E (2022) The ABC of hypoxia – what is the norm. https://doi.org/10.26124/mitofit:2022-0025
::::* Baglivo E, Cardoso LHD, Cecatto C, Gnaiger E (2022) Statistical analysis of instrumental reproducibility as internal quality control in high-resolution respirometry. https://doi.org/10.26124/mitofit:2022-0018.v2
{{Template:Cited by Gnaiger 2021 Bioenerg Commun}}
::::* Vernerova A, Garcia-Souza LF, Soucek O, Kostal M, Rehacek V, Krcmova LK, Gnaiger E, Sobotka O (2021) Mitochondrial respiration of platelets: comparison of isolation methods. https://doi.org/10.3390/biomedicines9121859
{{Template:Cited by Gnaiger 2021 MitoFit BCA}}
{{Template:Cited by Krako Jakovljevic 2021 BEC PD}}
{{Template:Cited by Komlodi 2021 MitoFit CoQ}}
{{Template:Cited by Komlodi 2021 MitoFit CoQ}}
{{Template:Cited by Cardoso 2021 MitoFit MgG}}
{{Template:Cited by Cardoso 2021 MitoFit MgG}}
{{Template:Cited by Went 2021 MitoFit PB}}
{{Template:Cited by Went 2021 MitoFit PB}}
{{Template:Cited by Huete-Ortega M 2021 MitoFit Dark respiration}}
{{Template:Cited by Silva 2021 MitoFit Etomoxir}}
 
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{{Labeling
{{Labeling
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|pathways=F, N, S, Gp, CIV, NS, ROX
|pathways=F, N, S, Gp, CIV, NS, ROX
|instruments=Oxygraph-2k, O2k-Fluorometer, O2k-Protocol, Theory
|instruments=Oxygraph-2k, O2k-Fluorometer, O2k-Protocol, Theory
|additional=BEC, BEC2020, MitoFitPublication, MitoEAGLEPublication, MitoPathways, O2k-chemicals and media, Mt-preparations, O2k-Demo, O2k-Core, 1R;2Omy;3U-, 1PGM;2D;3U-, 1PGM;2D;2c;3S;4U;5Rot;6Ama, 1OctM;2D;3G;4S;5U;6Rot;7Ama, Activity, Advancement, Amount of substance, Ampere, Assay, Avogadro constant, Barometric pressure, Biochemical coupling efficiency, Body mass, Boltzmann constant, Cell count and normalization in HRR, Cell respiration, Charge number, Citrate synthase activity, Closed chamber, Concentration, Count, Coupling-control ratio, Density, Dimension, Efficiency, Electric current, Electrochemical constant, Electron transfer pathway, Elementary charge, Elementary entity, Energy, Entity, ET capacity, Extensive quantity, E-L coupling efficiency, E-L net ET capacity, E-P excess capacity, E-P control efficiency, E-R reserve capacity, E-R control efficiency, Elementary charge, Faraday constant, Flow, Flux, Flux control efficiency, Flux control ratio, Force, Format, Gas constant, High-resolution respirometry, Iconic symbols, International System of Units, Isolated mitochondria, LEAK-respiration, Living cells, L/P coupling control ratio, L/R coupling control ratio, Malic enzyme, Mass, Mitochondrial marker, Mole, Motive unit, Normalization of rate, Number, Open chamber, OXPHOS capacity, OXPHOS-control ratio, Oxygen flow, Oxygen pressure, Oxygen solubility, Power, P-L net OXPHOS capacity, Pascal, Pathway control ratio, Permeabilized cells, Pressure, P-L control efficiency, Pressure, Protonmotive force, Quantities, Quantity, Reproducibility crisis, Residual oxygen consumption, Respirometry, ROUTINE-control ratio, ROUTINE-coupling efficiency R-L, ROUTINE respiration, R-L net ROUTINE capacity, Sample, SI prefixes, Solubility, Solutions, Specific quantity, Symbols, System, Unit, Volume, Work, BEC 2020.1, X-mass Carol, MitoFit 2021 MgG, MitoFit 2021 CoQ, MitoFit 2021.5 PB, MitoFit 2021 Dark respiration
|additional=Additivity, BEC, BEC2020, MitoFitPublication, MitoEAGLEPublication, MitoPathways, O2k-chemicals and media, Mt-preparations, O2k-Demo, O2k-Core, 1R;2Omy;3U-, 1PGM;2D;3U-, 1PGM;2D;2c;3S;4U;5Rot;6Ama, 1OctM;2D;3G;4S;5U;6Rot;7Ama, Activity, Advancement, Amount of substance, Ampere, Assay, Avogadro constant, Barometric pressure, Biochemical coupling efficiency, Body mass, Boltzmann constant, Cell count and normalization in HRR, Cell respiration, Charge number, Citrate synthase activity, Closed chamber, Concentration, Count, Coupling-control ratio, Density, Dimension, Efficiency, Electric current, Electrochemical constant, Electron transfer pathway, Elementary charge, Elementary entity, Energy, Entity, ET capacity, Extensive quantity, E-L coupling efficiency, E-L net ET capacity, E-P excess capacity, E-P control efficiency, E-R reserve capacity, E-R control efficiency, Elementary charge, Faraday constant, Flow, Flux, Flux control efficiency, Flux control ratio, Force, Format, Gas constant, High-resolution respirometry, Iconic symbols, International System of Units, Isolated mitochondria, LEAK-respiration, Living cells, L/P coupling control ratio, L/R coupling control ratio, Malic enzyme, Mass, Mitochondrial marker, Mole, Motive unit, Normalization of rate, Number, Open chamber, OXPHOS capacity, OXPHOS-control ratio, Oxygen flow, Oxygen pressure, Oxygen solubility, Power, P-L net OXPHOS capacity, Pascal, Pathway control ratio, Permeabilized cells, Pressure, P-L control efficiency, Pressure, Protonmotive force, Quantities, Quantity, Reproducibility crisis, Residual oxygen consumption, Respiratory states, Respirometry, ROUTINE-control ratio, ROUTINE-coupling efficiency R-L, ROUTINE respiration, R-L net ROUTINE capacity, Sample, SI prefixes, Solubility, Solutions, Specific quantity, Symbols, System, Unit, Volume, Work,  
BEC 2020.1, X-mass Carol, MitoFit 2021 MgG, MitoFit 2021 CoQ, MitoFit 2021.5 PB, MitoFit 2021 BCA, MitoFit 2021 PLT, BEC2021.5, PLoSONE2022ace-sce, MitoFit2022Hypoxia, MitoFit 2022 NADH, MitoFit 2022 pmF, MitoFit2022QC
}}
}}
{{MitoPedia topics
{{MitoPedia topics
|mitopedia topic=BEC
|mitopedia topic=BEC
}}
}}

Revision as of 18:02, 17 September 2022


Bioenergetics Communications        
Gnaiger 2020 BEC MitoPathways
       
Gnaiger Erich et al ― MitoEAGLE Task Group (2020) Mitochondrial physiology. Bioenerg Commun 2020.1.
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Bioenergetics Communications
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Publications in the MiPMap
Gnaiger E (2020) Mitochondrial pathways and respiratory control. An introduction to OXPHOS analysis. 5th ed. https://doi.org/10.26124/bec:2020-0002

» Bioenerg Commun 2020.2:112 pp. Open Access pdf published online 2020-12-30

Gnaiger Erich (BEC 2020.2) Bioenerg Commun

Abstract: BEC.png https://doi.org/10.26124/bec:2020-0002

Did you know that keeping your mitochondria fit is essential for quality of life, brain and muscle function, and resistance against preventable, immunological, and age-related degenerative diseases?

The capacity of cellular oxidative phosphorylation (OXPHOS) — a direct measure of mitochondrial function — is a result of evolution, age, gender, lifestyle, and environment (EAGLE). Increasingly, western lifestyle and aging contribute to mitochondrial dysfunction and the current epidemic of preventable diseases, including neurodegenerative and cardiovascular diseases, obesity, diabetes, and various types of cancer. The mitObesity epidemic leads to multimorbidity in aging and threatens to overwhelm the capacity of healthcare systems.

Training in mitochondrial physiology and bioenergetics, therefore, has high relevance to society. The ‘Blue Book’ on Mitochondrial Pathways and Respiratory Control presents a fundamental introduction to OXPHOS analysis for students and researchers in life sciences ― from evolutionary biology to medical and environmental applications. It combines concepts of bioenergetics and biochemical pathways related to mitochondrial core energy metabolism, provides the basis for substrate-uncoupler-inhibitor titration (SUIT) protocols, and updates the terminology consistent with the MitoEAGLE white paper on Mitochondrial Physiology.

It is now our responsibility to transfer the enthusiasm for innovation, reproducibility, and quality in science, and to translate mitochondrial research into visionary healthcare solutions.

Keywords: Q-junction, Respiratory states, Flux control ratios, Additivity, Body mass excess Bioblast editor: Gnaiger E O2k-Network Lab: AT Innsbruck Gnaiger E, AT Innsbruck Oroboros

ORCID: ORCID.png Gnaiger Erich

The Blue Book

MitoPathways Supplement s1: Poster


Gnaiger 2020 BEC MitoPathways

A guide through the chapters


  1. Real-time OXPHOS analysis. — Richard Altmann’s bioblasts are the systematic unit of bioenergetics and chemiosmotic coupling studied in living cells and mitochondrial preparations. A rigorous understanding of mitochondrial respiratory control relies on a clear concept of metabolic states and rates, accurate measurement and normalization of oxygen flux, and analysis of mitochondrial pathways.
  2. Respiratory states and rates: coupling control. — A concept-driven terminology frames our perception of the meaning of respiratory states and rates, from ROUTINE respiration of living cells to the capacity of oxidative phosphorylation (OXPHOS) determined in mitochondrial preparations, electron transfer (ET) capacity, LEAK respiration, and the distinction of uncoupled, noncoupled, or dyscoupled respiration.
  3. Normalization of rate: flow, flux, and flux ratios. — ‘The challenges of measuring respiratory rate are matched by those of normalization’ (Gnaiger et al 2000). The effect of metabolic control variables on flow or flux can be expressed by normalization for rate in a reference state, and is evaluated relative to a background state. The concept of flux control efficiency is based on principles of thermodynamics and is guided by statistical considerations, to remove the bias of the classical respiratory control ratio.
  4. NADH-linked pathways through Complex CI: respiratory pathway control with pyruvate, glutamate, malate. — Substrate combinations feeding electrons into the ET system through NADH have been considered to reflect physiological respiratory states in mitochondrial preparations. These protocols ignored the importance of cataplerotic metabolite depletion in the tricarboxylic acid (TCA) cycle.
  5. S-pathway through Complex CII, F-pathway through CETF, Gp-pathway through CGpDH. — Succinate as the substrate of CII is at a level comparable to NADH as the substrate for CI. Too many textbooks and publications propagate the error of comparing NADH in the N-pathway with FADH2 in the S-pathway ― together with fumarate, FADH2 is a product but not a substrate of CII.
  6. NS-pathway through Complexes CI & CII: convergent electron transfer at the Q-junction. — The term ‘electron transport chain’ is a misnomer in bioenergetics, conceiling the convergent pathway architecture of the electron transfer system (ETS). This has direct implications on the design of substrate-uncoupler-inhibitor titration (SUIT) protocols, for reconstitution of TCA cycle function, and sequential separation of branches of mitochondrial pathways for OXPHOS analysis.
  7. Additivity of convergent electron transfer. — OXPHOS capacity depends on the degree of additivity of pathways converging at the Q-junction. Paradoxically, current concepts on interaction do not agree whether to categorize incompletely additive effects as synergistic or antagonistic. A new mathematical definition of additivity bridges the gap between these apparently incompatible models of interaction.
  8. Protonmotive pressure and respiratory control. — Why is thermodynamics scary? The driving force of chemical reactions is confusingly called an energy (Gibbs energy), whereas it is actually an isomorphic force, linked to the electric and chemical terms of the protonmotive force pmF. The gas law represents chemical force and gas pressure. Flux-force relations are non-linear. Why should we consider Fick’s linear law of diffusion and protonmotive pressure in the control of flux?
» BEC tutorial-Living Communications: pmF to pmP
Gnaiger 2020 BEC MitoPathways

Preface

Blue book banner.jpg
Figure 1. The Blue Book: Mitochondrial Pathways and Respiratory Control 1st edition (2007). 1st Mitochondrial Physiology Summer School, MiPsummer July 2007, Schröcken, Austria.
Mitochondrial physiology is part of our lives. Mitochondrial fitness — the capacity of oxidative phosphorylation (OXPHOS) — is essential for the quality of your life, for brain and muscle function, for resistance against preventable and age-related degenerative diseases. Evolutionary background, age, gender (sex), lifestyle, and environmental factors (EAGLE) determine mitochondrial fitness, which is OXPHOS capacity and multiple mitochondrial functions. Comprehensive OXPHOS analysis is vital for understanding your cells, vital for our health care systems, and vitally deserves reliability and reproducibility of analytical and diagnostic studies.
The Blue Book on Mitochondrial Pathways and Respiratory Control presents a fundamental introduction to OXPHOS analysis. It combines concepts of bioenergetics and biochemical pathways related to mitochondrial (mt) core energy metabolism and provides the basis for the substrate-uncoupler-inhibitor titration (SUIT) protocols in high-resolution respirometry, which have been established since publication of the first edition of MitoPathways in 2007 (Figure 1).
Figure 2.
Application of SUIT protocols for real-time OXPHOS analysis is a component of metabolic phenotyping (Figure 2). OXPHOS analysis extends conventional bioenergetics to the level of mitochondrial physiology for functional diagnosis in health and disease. The Oroboros O2k for HRR has the high signal stability and unrestricted flexibility of titrations suited for application of elementary and complex SUIT protocols.
Since 2007, research in mitochondrial physiology sparked a revolution of bioenergetics by experimental design that appreciates the convergent architecture of the electron transfer system (ETS) with multiple branches of mitochondrial pathways converging at the Q-junction, leading to a novel concept of additivity introduced in the new Chapter 7 of the Blue Book. These advancements are documented by >1 000 reports listed under 'NS-pathway control state' in MitoPedia. To study respiratory control at the Q-junction, SUIT protocols are applied with physiological substrate cocktails, particularly NADH-linked substrates (N) in combination with succinate (NS), fatty acids (FNS), and glycerophosphate (FNSGp), which have been introduced for the first time in the 1st edition of MitoPathways (2007).
Since then, ‘MitoPedia’ was initiated and the COST Action MitoEAGLE flies. 666 coauthors joined forces to present a harmonized nomenclature on Mitochondrial Physiology (Bioenerg Commun 2020.1), with an emphasis on conceptual consistency for establishing a quality-controlled database on mitochondrial respiratory physiology. The 5th edition of MitoPathways gained from this collaboration. Many terms and symbols are simplified or presented in a more explicit form compared to the 2014 edition. Terms and iconic symbols develop meaning in context. Contextual meaning is best communicated by stories told in entertaining lectures, or by equations even if they turn off the most motivated student. Motivation is never enough. We need passion, persistence, resilience to transpose equations, terms and stories into the domain of personal experience, gaining perspective from perception to conception. The best scientific experience is the experiment driven by a hypothetical story written in clear words and forged into meaningful equations. This may provide a guideline to the critical discussion of the ergodynamic concept of the protonmotive force and chemiosmotic pressure, inspired by the Grey Book of Peter Mitchell and added as the new Chapter 8 of the Blue Book.
Mitochondria are the structural and functional elementary units of cell respiration. MitoPathways is an element of the Oroboros Ecosystem driven by high-resolution respirometry and shaping mitochondrial physiology. A mosaic evolves by combining the elements into a picture of modern mitochondrial respiratory physiology.
I thank all collaborators of the NextGen-O2k project and the authors and coauthors of various publications emerging from international cooperations, particularly the Horizon 2020 funded COST Action CA15203 MitoEAGLE. Without the team at Oroboros Instruments, including our partners in electromechanical engineering (O2k; WGT-Elektronik, Kolsass, Austria) and DatLab software development the experimental advances on MitoPathways would not have been possible.
Erich Gnaiger
Innsbruck, 2007 - 2020


Acknowledgements

Specific thanks is extended to Oroboros team members Luiza Cardoso, Cristiane Cecatto, Carolina Doerrier, Sabine Schmitt, Timea Komlódi, Zulfiya Orynbayeva, and Lucie Zdrazilova for critical reading and helpful suggestions on various chapters, and to Univ.-Prof. Dr. Markus Haltmeier (Applied Mathematics, Univ Innsbruck, Austria) for stimulating discussions on additivity (Chapter 7).
Gnaiger 2020 BEC MitoPathways

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Chapters: References and notes

References Preface
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  2. Gnaiger E ed (2007) Mitochondrial pathways and respiratory control. 1st ed. Oroboros MiPNet Publications, Innsbruck:96 pp. - »Bioblast link«
  3. Gnaiger E et al ― MitoEAGLE Task Group (2020) Mitochondrial physiology. Bioenerg Commun 2020.1. https://doi.org/bec:2020-0001.v1
» MitoPedia: Terms and abbreviations
Gnaiger 2020 BEC MitoPathways
Figure 1.1. Coupling in oxidative phosphorylation is mediated by the protonmotive force pmF.

Chapter 1. Real-time OXPHOS analysis

Figure 1.2.

References: 1. OXPHOS

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  31. Renner K , Amberger A, Konwalinka G, Gnaiger E (2003) Changes of mitochondrial respiration, mitochondrial content and cell size after induction of apoptosis in leukemia cells. - »Bioblast link« -
    Figure 1.6A.
  32. Rossignol R, Faustin B, Rocher C, Malgat M, Mazat JP, Letellier T (2003) Mitochondrial threshold effects. - »Bioblast link«
  33. Saks VA, Veksler VI, Kuznetsov AV, Kay L, Sikk P, Tiivel T, Tranqui L, Olivares J, Winkler K, Wiedemann F, Kunz WS (1998) Permeabilised cell and skinned fiber techniques in studies of mitochondrial function in vivo. - »Bioblast link« - The apparent Km for ADP increases up to 0.5 mM in some permeabilized muscle fibres.
  34. Territo PR, Mootha VK, French SA, Balaban RS (2000) Ca2+ activation of heart mitochondrial oxidative phosphorylation: role of the FO/F1-ATPase. - »Bioblast link«

Notes: OXPHOS

  1. Mitochondrial markers
Gnaiger 2020 BEC MitoPathways
States 1-2-3-4-5.jpg
RCR and OXPHOS coupling eff.jpg

Chapter 2. Respiratory states and rates: coupling control

References: 2. States and rates

  1. Chance B, Williams GR (1955) Respiratory enzymes in oxidative phosphorylation. I. Kinetics of oxygen utilization. - »Bioblast link«
  2. Chance B, Williams GR (1955) Respiratory enzymes in oxidative phosphorylation. III. The steady state. - »Bioblast link«
  3. Chance B, Williams GR (1956) The respiratory chain and oxidative phosphorylation. - »Bioblast link«
  4. Estabrook R (1967) Mitochondrial respiratory control and the polarographic measurement of ADP:O ratios. - »Bioblast link«
  5. Gnaiger E (2001) Bioenergetics at low oxygen: dependence of respiration and phosphorylation on oxygen and adenosine diphosphate supply. - »Bioblast link«
  6. Gnaiger Erich et al ― MitoEAGLE Task Group (2020) Mitochondrial physiology. https://doi.org/10.26124/bec:2020-0001.v1. - »Bioblast link«
  7. Gnaiger E, Lassnig B, Kuznetsov AV, Margreiter R (1998) Mitochondrial respiration in the low oxygen environment of the cell: Effect of ADP on oxygen kinetics. - »Bioblast link« - Oxygen kinetics is different in the LEAK state without adenylates (LN) and State 4 (LEAK state with ATP, LN).
  8. Gnaiger E, Méndez G, Hand SC (2000) High phosphorylation efficiency and depression of uncoupled respiration in mitochondria under hypoxia. - »Bioblast link«
  9. König T, Nicholls DG, Garland PB (1969) The inhibition of pyruvate and Ls(+)-isocitrate oxidation by succinate oxidation in rat liver mitochondria. - »Bioblast link« - 3½ has been suggested to indicate an intermediate mitochondrial energy state somewhere between States 3 and 4. Would, therefore, State 4 be considered as being somewhere between State 3 and 5?
  10. Krumschnabel G, Eigentler A, Fasching M, Gnaiger E (2014) Use of safranin for the assessment of mitochondrial membrane potential by high-resolution respirometry and fluorometry. - »Bioblast link«
  11. Singh Simon (1997) Fermat's last theorem. Fourth Estate, London 340 pp. - »Bioblast link«
Figure 2.4.

Notes: Coupling states

» MitoPedia: Respiratory states OXPHOS ROUTINE ET capacity LEAK - ROX
  1. A colour code is used with red and green in analogy to the states at a traffic light: at red, the motor is running in neutral gear (uncoupled) at minimum turnover without output (producing some heat) just to keep the engine running; at green, the motor is switched into gear and driven in a coupled state with full output. The blue colour is used to indicate a state of maximum input in neutral gear, or pressing fully the accelerator and the clutch simultaneously, which yields maximum turnover without output and produces a maximum of heat. The analogy for coupling in OXPHOS and in cars has its limitations but may help to memories the red/green colour code - you may think of it when your car is in a LEAK at the next red traffic light.
  2. H+ translocation through pumps is shown by dotted arrows across the mtIM.
Gnaiger 2020 BEC MitoPathways

Chapter 3. Normalization of rate: flow, flux, and flux ratios

References: 3. Normalization

  1. Aguirre E, Rodríguez-Juárez F, Bellelli A, Gnaiger E, Cadenas S (2010) Kinetic model of the inhibition of respiration by endogenous nitric oxide in intact cells. - »Bioblast link« - Tables 3.1 and 3.2: HEK 293
  2. Chance B, Williams GR (1955) Respiratory enzymes in oxidative phosphorylation. I. Kinetics of oxygen utilization. - »Bioblast link«
  3. Chance B, Williams GR (1955) Respiratory enzymes in oxidative phosphorylation. III. The steady state. - »Bioblast link«
  4. Doerrier C, Garcia-Souza LF, Krumschnabel G, Wohlfarter Y, Mészáros AT, Gnaiger E (2018) High-Resolution FluoRespirometry and OXPHOS protocols for human cells, permeabilized fibers from small biopsies of muscle, and isolated mitochondria. - »Bioblast link«
  5. Gnaiger E (2001) Bioenergetics at low oxygen: dependence of respiration and phosphorylation on oxygen and adenosine diphosphate supply. - »Bioblast link«
  6. Hütter E, Renner K, Pfister G, Stöckl P, Jansen-Dürr P, Gnaiger E (2004) Senescence-associated changes in respiration and oxidative phosphorylation in primary human fibroblasts. - »Bioblast link« - Tables 3.1 and 3.2: fibrolasts; Figure 3.1.
  7. Hütter E, Unterluggauer H, Garedew A, Jansen-Dürr P, Gnaiger E (2006) High-resolution respirometry - a modern tool in aging research. - »Bioblast link«
  8. Renner K, Amberger A, Konwalinka G, Gnaiger E (2003) Changes of mitochondrial respiration, mitochondrial content and cell size after induction of apoptosis in leukemia cells. - »Bioblast link« - Tables 3.1 and 3.2: CEM
  9. Stadlmann S, Renner K, Pollheimer J, Moser PL, Zeimet AG, Offner FA, Gnaiger E (2006) Preserved coupling of oxidative phosphorylation but decreased mitochondrial respiratory capacity in IL-1ß treated human peritoneal mesothelial cells. - »Bioblast link«


Questions.jpg


Click to expand or collaps
Bioblast links: Coupling control - >>>>>>> - Click on [Expand] or [Collapse] - >>>>>>>

1. Mitochondrial and cellular respiratory rates in coupling-control states

OXPHOS-coupled energy cycles. Source: The Blue Book
» Baseline state
Respiratory rate Defining relations Icon
OXPHOS capacity P = -Rox P.jpg mt-preparations
ROUTINE respiration R = -Rox R.jpg living cells
ET capacity E = -Rox E.jpg » Level flow
» Noncoupled respiration - Uncoupler
LEAK respiration L = -Rox L.jpg » Static head
» LEAK state with ATP
» LEAK state with oligomycin
» LEAK state without adenylates
Residual oxygen consumption Rox L = -Rox ROX.jpg
  • Chance and Williams nomenclature: respiratory states
» State 1 —» State 2 —» State 3 —» State 4 —» State 5

2. Flux control ratios related to coupling in mt-preparations and living cells

» Flux control ratio
» Coupling-control ratio
» Coupling-control protocol
FCR Definition Icon
L/P coupling-control ratio L/P L/P coupling-control ratio » Respiratory acceptor control ratio, RCR = P/L
L/R coupling-control ratio L/R L/R coupling-control ratio
L/E coupling-control ratio L/E L/E coupling-control ratio » Uncoupling-control ratio, UCR = E/L (ambiguous)
P/E control ratio P/E P/E control ratio
R/E control ratio R/E R/E control ratio » Uncoupling-control ratio, UCR = E/L
net P/E control ratio (P-L)/E net P/E control ratio
net R/E control ratio (R-L)/E net R/E control ratio

3. Net, excess, and reserve capacities of respiration

Respiratory net rate Definition Icon
P-L net OXPHOS capacity P-L P-L net OXPHOS capacity
R-L net ROUTINE capacity R-L R-L net ROUTINE capacity
E-L net ET capacity E-L E-L net ET capacity
E-P excess capacity E-P E-P excess capacity
E-R reserve capacity E-R E-R reserve capacity

4. Flux control efficiencies related to coupling-control ratios

» Flux control efficiency jZ-Y
» Background state
» Reference state
» Metabolic control variable
Coupling-control efficiency Definition Icon Canonical term
P-L control efficiency jP-L = (P-L)/P = 1-L/P P-L control efficiency P-L OXPHOS-flux control efficiency
R-L control efficiency jR-L = (R-L)/R = 1-L/R R-L control efficiency R-L ROUTINE-flux control efficiency
E-L coupling efficiency jE-L = (E-L)/E = 1-L/E E-L coupling efficiency E-L ET-coupling efficiency » Biochemical coupling efficiency
E-P control efficiency jE-P = (E-P)/E = 1-P/E E-P control efficiency E-P ET-excess flux control efficiency
E-R control efficiency jE-R = (E-R)/E = 1-R/E E-R control efficiency E-R ET-reserve flux control efficiency

5. General

» Basal respiration
» Cell ergometry
» Dyscoupled respiration
» Dyscoupling
» Electron leak
» Electron-transfer-pathway state
» Hyphenation
» Oxidative phosphorylation
» Oxygen flow
» Oxygen flux
» Permeabilized cells
» Phosphorylation system
» Proton leak
» Proton slip
» Respiratory state
» Uncoupling


Figure 4.3.
Gnaiger 2020 BEC MitoPathways

Chapter 4. NADH-linked pathways through Complex I: respiratory pathway control with pruvate, glutamate, malate

References: 4. N-pathways

  1. Brandt U (2006) Energy converting NADH:quinone oxidoreductase (Complex I). Annu Rev Biochem 75:69-92.
  2. Brewer GJ, Jones TT, Wallimann T, Schlattner U (2004) Higher respiratory rates and improved creatine stimulation in brain mitochondria isolated with antioxidants. - »Bioblast link«
  3. Chance B, Williams GR (1955) Respiratory enzymes in oxidative phosphorylation. III. The steady state. - »Bioblast link« - Substrate depletion in isolated mitochondria is achieved in State 2: ADP is added to induce a transient stimulation of oxygen flux based on oxidation of endogenous substrates.
  4. Digerness SB, Reddy WJ (1976) The malate-aspartate shuttle in heart mitochondria. J Mol Cell Cardiol. 8:779-85.
  5. Duchen MR (2004) Roles of mitochondria in health and disease. Diabetes 53, Suppl 1:S96-102. - Mitochondrial glutamate dehydrogenase is particularly active in astrocytes, preventing glutamate induced neurotoxicity.
  6. Gnaiger E (2009) Capacity of oxidative phosphorylation in human skeletal muscle. New perspectives of mitochondrial physiology. - »Bioblast link«
  7. Gnaiger E, Méndez G, Hand SC (2000) High phosphorylation efficiency and depression of uncoupled respiration in mitochondria under hypoxia. - »Bioblast link« - Equilibrium ratio of malate to fumarate is 4.1.
  8. Hildyard JCW, Halestrap AP (2003) Identification of the mitochondrial pyruvate carrier in Saccharomyces cerevidiae. Biochem J 374:607-11.
  9. Johnson G, Roussel D, Dumas JF, Douay O, Malthiery Y, Simard G, Ritz P (2006) Influence of intensity of food restriction on skeletal muscle mitochondrial energy metabolism in rats. Am J Physiol Endocrinol Metab 291:E460-7. - Uncoupling stimulates coupled OXPHOS respiration, PMP, by 14 %.
  10. Kemp RB, Hoare S, Schmalfeldt M, Bridge CM, Evans PM, Gnaiger E (1994) A thermochemical study of the production of lactate by glutaminolysis and glycolysis in mouse macrophage hybridoma cells. - »Bioblast link« - Glutamate derived from hydrolyzation of glutamine is a very important aerobic substrate in cultured cells.
  11. Lemasters JJ (1984) The ATP-to-oxygen stoichiometries of oxidative phosphorylation by rat liver mitochondria. - »Bioblast link« - Malonate added to inhibit the succinate-fumarate reaction exerts only a minor effect on liver mitochondrial respiration.
  12. Maechler P, Carobbio S, Rubi B (2006) In beta-cells, mitochondria integrate and generate metabolic signals controlling insulin secretion. Int J Biochem Cell Biol 38:696-709.
  13. Messer JI, Jackman MR, Willis WT (2004) Pyruvate and citric acid cycle carbon requirements in isolated skeletal muscle mitochondria. - »Bioblast link« - With malate alone and saturating [ADP] isolated rat skeletal muscle mitochondria respire at only 1.3 % of OXPHOS capacity with pyruvate+malate. Pyruvate alone yields only 2.1 % of OXPHOS capacity (P) with PM.
  14. Nicholls DG, Ferguson SJ (2002) Bioenergetics 3. - »Bioblast link« - Carriers.
  15. Ouhabi R, Boue-Grabot M, Mazat J-P (1994) ATP synthesis in permeabilized cells: Assessment of the ATP/O ratios in situ. - »Bioblast link« - In fibroblasts, GMP supports a higher respiratory flux than PMP.
  16. O’Donnell JM, Kudej RK, LaNoue KF, Vatner SF, Lewandowski ED (2004) Limited transfer of cytosolic NADH into mitochondria at high cardiac workload. Am J Physiol Heart Circ Physiol 286:H2237-42.
  17. Puchowicz MA, Varnes ME, Cohen BH, Friedman NR, Kerr DS, Hoppel CL (2004) Oxidative phosphorylation analysis: assessing the integrated functional activity of human skeletal muscle mitochondria – case studies. - »Bioblast link« - OXPHOS with glutamate alone is 50 % to 85 % of respiration with glutamate&malate. Accumulation of fumarate inhibits succinate dehydrogenase and glutamate dehydrogenase (Caughey et al 1957; Dervartanian, Veeger 1964). - OXPHOS with glutamate&malate is identical or 10 % higher than with pyruvate&malate.
  18. Rasmussen UF, Rasmussen HN (2000) Human quadriceps muscle mitochondria: A functional characterization. - »Bioblast link« - Uncoupling stimulates coupled OXPHOS respiration, PMP, by 15 % in human skeletal muscle. OXPHOS with glutamate alone is 50 % to 85 % of respiration with glutamate&malate. - OXPHOS with glutamate&malate is identical or 10 % higher than with pyruvate&malate.
  19. Schöpf B, Weissensteiner H, Schäfer G, Fazzini F, Charoentong P, Naschberger A, Rupp B, Fendt L, Bukur V, Giese I, Sorn P, Sant’Anna-Silva AC, Iglesias-Gonzalez J, Sahin U, Kronenberg F, Gnaiger E, Klocker H (2020) OXPHOS remodeling in high-grade prostate cancer involves mtDNA mutations and increased succinate oxidation. - »Bioblast link«
  20. Swenson ER (2018) Does aerobic respiration produce carbon dioxide or hydrogen ion and bicarbonate? - »Bioblast link«
  21. Thomas et al (2004) - OXPHOS in human skeletal muscle for PMP is 25 % higher than for GMP.
  22. Winkler-Stuck K, Kirches E, Mawrin C, Dietzmann K, Lins H, Wallesch CW, Kunz WS, Wiedemann FR (2005) Re-evaluation of the dysfunction of mitochondrial respiratory chain in skeletal muscle of patients with Parkinson's disease. - »Bioblast link« - OXPHOS in human skeletal muscle for PMP is 16% higher than for GMP.
  23. MitoPedia
» Malic enzyme
N-junction

Notes: N-pathways

  1. N-pathway control state
  2. The metabolic maps in this and the following chapters have been modified and extended in comparison to previous editions. Added substrates are printed in blue in contrast to intermediates printed in black. CI-linked substrates and intermediates are shown with white background, whereas added succinate and consecutively formed fumarate are distinguished with a yellow background (FADH2 and the corresponding arrows are emphasized by yellow shades). Intermediates with grey background are considered to be present at low concentrations due to metabolite depletion, whereas products with blue background are considered to accumulate in the matrix space or in equilibrium with the large volume of incubation medium or to increase in equilibrium with the supplied substrate.
  3. Schwerzmann et al (1989) Proc Natl Acad Sci U S A 86:1583-7. - “Of the substrates used here, pyruvate/malate activates the chain at complex I, glutamate/malate and succinate at complexes II and III, ..” - This consideration of glutamate&malate requires correction.
  4. Ponsot et al (2005) J Cell Physiol 203:479-86. - (a) Respiration (State 3) in permeabilized fibres with malate alone gave 25-50 % of the flux with pyruvate+malate. This needs to be discussed in terms of endogenous mitochondrial substrates, which interfere to an unknown degree with the kinetics of respiration after addition of exogenous substrates, or the activity of malic enzyme. (b) Maximal respiration rates in muscle should be evaluated at saturating or high Pi, since at a Pi concentration of 3 mM OXPHOS respiration may be phosphate limited.
  5. Hulbert et al (2006) J Comp Physiol B 176:93-105. Addition of ‘sparking malate concentrations’. This term can probably be derived from the misconception that tricarboxylic acid cycle intermediates are conserved during respiration of isolated mitochondria. 380 µM malate in conjunction with 2.4 mM pyruvate were used, which makes a comparison difficult between different tissues and different species: the low substrate concentrations may limit PMP flux at various degrees in the different sources of mitochondria, and GMP or PGMP may support higher fluxes than PMP at tissue- and species-specific degrees.


Figure 5.1.
Gnaiger 2020 BEC MitoPathways

Chapter 5. S-pathway through Complex II, F-pathway through electron-transferring flavoprotein, Gp-pathway through glycerophosphate dehydrogenase

References: 5. S-, F-, Gp-pathways

  1. Capel F, Rimbert V, Lioger D, Diot A, Rousset P, Patureau Mirand P, Boirie Y, Morio B, Mosoni L (2005) Due to reverse electron transfer, mitochondrial H2O2 release increases with age in human vastus lateralis muscle although oxidative capacity is preserved. Mech Ageing Develop 126:505-11. - With succinate alone OXPHOS is 30-40% lower than with succinate+rotenone in human skeletal muscle mitochondria.
  2. Cecchini G (2003) Function and structure of Complex II of the respiratory chain. Annu Rev Biochem 72:77-109.
  3. Ernster L, Nordenbrand K (1967) Skeletal muscle mitochondria. In: Estabrook RW, Pullman ME (eds) Meth Enzymol:86-94. – With succinate alone OXPHOS is 30-40% lower than with succinate+rotenone in rat skeletal muscle mitochondria.
  4. Jackman MR, Willis WT (1996) Characteristics of mitochondria isolated from type I and type IIb skeletal muscle. Am J Physiol Cell Physiol 270:C673-8. - Glycerophosphate oxidation is 10-fold higher in rabbit gracilis mitochondria compared to soleus.
  5. Lehninger AL (1970) Biochemistry. The molecular basis of cell structure and function Worth:833 pp. - Oxaloacetate is a more potent competitive inhibitor of succinate dehydrogenase than malonate even at small concentration (p 352).
  6. Muller FL, Liu Y, Abdul-Ghani MA, Lustgarten MS, Bhattacharya A, Jang YC, Van Remmen H (2008) High rates of superoxide production in skeletal-muscle mitochondria respiring on both Complex I- and Complex II-linked substrates. - »Bioblast link« - Addition of malate inhibits superoxide production with succinate, probably due to the oxaloacetate inhibition of CII.
  7. Rasmussen UF, Rasmussen HN (2000) Human quadriceps muscle mitochondria: A functional characterization. - »Bioblast link« – Glycerophosphate oxidation is relatively slow.
  8. Rauchova H, Drahota Z, Rauch P, Fato R, Lenaz G (2003) Coenzyme Q releases the inhibitory effect of free fatty acids on mitochondrial glycerophosphate dehydrogenase. Acta Biochim Polonica 50:405-13. - Glycerophosphate is an important substrate for respiration in brown adipose tissue mitochondria.
  9. Sun F, Huo X, Zhai Y, Wang A, Xu J, Su D, Bartlam M, Rao Z (2005) Crystal structure of mitochondrial respiratory membrane protein Complex II. Cell 121:1043–57.
  10. MitoPedia
» Complex II-linked substrate state •• Complex II
» Glycerophosphate dehydrogenase complex •• Electron-transferring flavoprotein complex
Succinate

Notes: S-, F-, Gp-pathways

  1. Succinate pathway
  2. Ponsot et al (2005) J Cell Physiol 203:479-86. - ‘.. the mitochondrial form of GPDH, which produces FADH2 within the mitochondrial matrix and provides electrons to Compoex II of the phosphorylation chain’. – The mitochondrial glycerophosphate dehydrogenase complex (CGpDH), located on the outer side of the inner mitochondrial membrane, does not provide electrons to CII, but feeds electrons into the Q-cycle entirely independent of CII. FADH2 is not produced within the mitochondrial matrix. Electron transfer takes place from the mitochondrial inner membrane flavoprotein-linked glycerophosphate dehydrogenase complex to CoQ.
Gnaiger 2020 BEC MitoPathways
Figure 6.3.

Chapter 6. NS-pathway through Complexes CI & CII: convergent electron transfer at the Q-junction and additive effect of substrate combinations

References: 6. Q-junction

  1. Aragonés J, Schneider M, Van Geyte K, Fraisl P, Dresselaers T, Mazzone M, Dirkx R, Zacchigna S, Lemieux H, Jeoung NH, Lambrechts D, Bishop T, Lafuste P, Diez-Juan A, K Harten S, Van Noten P, De Bock K, Willam C, Tjwa M, Grosfeld A, Navet R, Moons L, Vandendriessche T, Deroose C, Wijeyekoon B, Nuyts J, Jordan B, Silasi-Mansat R, Lupu F, Dewerchin M, Pugh C, Salmon P, Mortelmans L, Gallez B, Gorus F, Buyse J, Sluse F, Harris RA, Gnaiger E, Hespel P, Van Hecke P, Schuit F, Van Veldhoven P, Ratcliffe P, Baes M, Maxwell P, Carmeliet P (2008) Deficiency or inhibition of oxygen sensor Phd1 induces hypoxia tolerance by reprogramming basal metabolism. - »Bioblast link« - OXPHOS analysis for phenotyping.
  2. Bianchi C, Genova ML, Parenti Castelli G, Lenaz G (2004) The mitochondrial respiratory chain is partially organized in a supercomplex assembly: kinetic evidence using flux control analysis. - »Bioblast link«
  3. Boushel R, Gnaiger E, Calbet JA, Gonzalez-Alonso J, Wright-Paradis C, Sondergaard H, Ara I, Helge JW, Saltin B (2011) Muscle mitochondrial capacity exceeds maximal oxygen delivery in humans. - »Bioblast link«
  4. Boushel R, Gnaiger E, Schjerling P, Skovbro M, Kraunsoe R, Flemming D (2007) Patients with Type 2 Diabetes have normal mitochondrial function in skeletal muscle. - »Bioblast link«
  5. Capel F, Rimbert V, Lioger D, Diot A, Rousset P, Patureau Mirand P, Boirie Y, Morio B, Mosoni L (2005) Due to reverse electron transfer, mitochondrial H2O2 release increases with age in human vastus lateralis muscle although oxidative capacity is preserved. Mech Ageing Develop 126:505-11. - NS-substrate combination.
  6. Chance B (1965) Reaction of oxygen with the respiratory chain in cells and tissues. J Gen Physiol 49:163-88. - Glutamate&succinate as respiratory substrate combination, without comparison of flux with different substrates.
  7. Costa LE, Boveris A, Koch OR, Taquini AC (1988) Liver and heart mitochondria in rats submitted to chronic hypobaric hypoxia. Am J Physiol Cell Physiol 255:C123-C9.
  8. Digerness SB, Reddy WJ (1976) The malate-aspartate shuttle in heart mitochondria. J Mol Cell Cardiol. 8:779-85.
  9. Eberhart K, Rainer J, Bindreither D, Ritter I, Gnaiger E, Kofler R, Oefner PJ, Renner K (2011) Glucocorticoid-induced alterations in mitochondrial membrane properties and respiration in childhood acute lymphoblastic leukemia. - »Bioblast link«
  10. Estabrook R (1967) Mitochondrial respiratory control and the polarographic measurement of ADP:O ratios. - »Bioblast link«
  11. Garait B, Couturier K, Servais S, Letexier D, Perrin D, Batandier C, Rouanet J-L, Sibille B, Rey B, Leverve X, Favier R (2005) Fat intake reverses the beneficial effects of low caloric intake on skeletal muscle mitochondrial H2O2 production. Free Radic Biol Med 39:1249–61. - GMP/GMSP substrate control ratio in skeletal muscle of rats fed on various diets ranges from 0.7 to 0.8.
  12. Gnaiger E (2009) Capacity of oxidative phosphorylation in human skeletal muscle. New perspectives of mitochondrial physiology. - »Bioblast link«
  13. Gnaiger E, Boushel R, Søndergaard H, Munch-Andersen T, Damsgaard R, Hagen C, Díez-Sánchez C, Ara I, Wright-Paradis C, Schrauwen P, Hesselink M, Calbet JAL, Christiansen M, Helge JW, Saltin B (2015) Mitochondrial coupling and capacity of oxidative phosphorylation in skeletal muscle of Inuit and caucasians in the arctic winter. - »Bioblast link«
  14. Gnaiger E, Wright-Paradis C, Sondergaard H, Lundby C, Calbet JA, Saltin B, Helge J, Boushel R (2005) High-resolution respirometry in small biopsies of human muscle: correlations with body mass index and age. - »Bioblast link«
  15. González-Flecha B, Cutrin JC, Boveris A (1993) Time course and mechanism of oxidative stress and tissue damage in rat liver subjected to in vivo ischemia-reperfusion. J Clin Invest 91:456-64. - Respiration was measured in states GSP and GMP.
  16. Gutman M, Coles CJ, Singer TP, Casida JE (1971) On the functional organization of the respiratory chain at the dehydrogenase-coenzyme Q junction. Biochemistry 10:2036-43.
  17. Hansford RG, Hogue BA, Mildaziene V (1997) Dependence of H2O2 formation by rat heart mitochondria on substrate availability and donor age. J Bioenerg Biomembr 29:89–95.
  18. Hatefi Y, Haavik AG, Fowler LR, Griffiths DE (1962) Studies on the electron transfer-pathway. XLII. Reconstitution of the electron transfer-pathway. - »Bioblast link«
  19. König T, Nicholls DG, Garland PB (1969) The inhibition of pyruvate and Ls(+)-isocitrate oxidation by succinate oxidation in rat liver mitochondria. - »Bioblast link«
  20. Krebs HA (1935) CXCVII. Metabolism of amino-acids. III. Deamination of amino-acids. Biochem J 29:1620-44.
  21. Kunz WS, Kudin A, Vielhaber S, Elger CE, Attardi G, Villani G (2000) Flux control of cytochrome c oxidase in human skeletal muscle. - »Bioblast link«
  22. Kuznetsov AV, Clark JF, Winkler K, Kunz WS (1996) Increase of flux control of cytochrome c oxidase in copper-deficient mottled brindled mice. - »Bioblast link«
  23. Kuznetsov AV, Strobl D, Ruttmann E, Königsrainer A, Margreiter R, Gnaiger E (2002) Evaluation of mitochondrial respiratory function in small biopsies of liver. - »Bioblast link« - S(Rot) alone supports a higher flux than GM in liver mitocondria.
  24. Kuznetsov AV, Winkler K, Kirches E, Lins H, Feistner H, Kunz WS (1997) Application of inhibitor titrations for the detection of oxidative phosphorylation defects in saponin-skinned muscle fibers of patients with mitochondrial diseases. - »Bioblast link« - OXPHOS with glutamate&malate is identical or 10 % higher than with pyruvate&malate.
  25. LaNoue KF, Bryla J, Williamson JR (1972) Feedback interactions in the control of citric acid cycle activity in rat heart mitochondria. - »Bioblast link«
  26. LaNoue KF, Schoolwerth AC (1979) Metabolite transport in mitochondria. Annu Rev Biochem 48:871-922.
  27. Lehninger AL (1970) Biochemistry. The molecular basis of cell structure and function Worth:833 pp. - Electron transport chain.
  28. Lemieux H, Blier PU, Gnaiger E (2017) Remodeling pathway control of mitochondrial respiratory capacity by temperature in mouse heart: electron flow through the Q-junction in permeabilized fibers. - »Bioblast link«
  29. Lemieux H, Semsroth S, Antretter H, Hoefer D, Gnaiger E (2011) Mitochondrial respiratory control and early defects of oxidative phosphorylation in the failing human heart. - »Bioblast link« - SUIT protocols.
  30. Lenaz G, Genova ML (2009) Structural and functional organization of the mitochondrial respiratory chain: A dynamic super-assembly. Int J Biochem Cell Biol 41:1750-72.
  31. Llesuy S, Evelson P, González-Flecha B, Peralta J, Carreras MC, Poderoso JJ, Boveris A (1994) Oxidative stress in muscle and liver of rats with septic syndrome. Free Radic Biol Med 16:445-51. - GMP/GSP substrate control ratios are 0.8 and 0.7 in liver mitochondria (male Wistar and female Sprague-Dawley, respectively).
  32. Mogensen M, Sahlin K (2005) Mitochondrial efficiency in rat skeletal muscle: influence of respiration rate, substrate and muscle type. Acta Physiol Scand 185:229-36. - The flux control ratio of palmitoylcarnitine&malate/PM (OXPHOS) is 0.6 for mitochondria isolated from rat extensor digitorum longus muscle (mainly type II fibre type), but is 0.95 in rat soleus muscle (type I fibre type).
  33. Muller FL, Liu Y, Abdul-Ghani MA, Lustgarten MS, Bhattacharya A, Jang YC, Van Remmen H (2008) High rates of superoxide production in skeletal-muscle mitochondria respiring on both Complex I- and Complex II-linked substrates. - »Bioblast link«
  34. Nicholls DG, Ferguson SJ (2002) Bioenergetics 3. - »Bioblast link« - Electron transport chain.
  35. Pesta D, Gnaiger E (2012) High-resolution respirometry. OXPHOS protocols for human cells and permeabilized fibres from small biopisies of human muscle. - »Bioblast link« - SUIT protocols.
  36. Pesta D, Hoppel F, Macek C, Messner H, Faulhaber M, Kobel C, Parson W, Burtscher M, Schocke M, Gnaiger E (2011) Similar qualitative and quantitative changes of mitochondrial respiration following strength and endurance training in normoxia and hypoxia in sedentary humans. - »Bioblast link« - SUIT protocols.
  37. Rasmussen HN, Rasmussen UF (1997) Small scale preparation of skeletal muscle mitochondria, criteria for integrity, and assays with reference to tissue function. Mol Cell Biochem 174:55-60.
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  57. MitoPedia
NS-pathway control state

Notes: Q-junction

  1. NS-pathway control state
  2. Identical GMP/GSP or GMP/GMSP ratios of 0.7 are reported for isolated mitochondria (Rasmussen and Rasmussen 2000; Capel et al 2005) and permeabilized fibres (Kunz et al 2000). For a review see Gnaiger (2009).


Gnaiger 2020 BEC MitoPathways

Chapter 7. Additivity of convergent electron transfer

References: 7. Additivity

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Gnaiger 2020 BEC MitoPathways
Vector flux and velocity

Chapter 8. Protonmotive pressure and respiratory control

» BEC tutorial-Living Communications: pmF to pmP

References: 8. Protonmotive pressure

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Gnaiger 2020 BEC MitoPathways

A. Conversions of metabolic fluxes

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Gnaiger 2020 BEC MitoPathways

B: SUIT

B1. Substrates, uncouplers and inhibitors

» MitoPedia: Substrates and metabolites
» MitoPedia: Uncouplers
» MitoPedia: Inhibitors
Gnaiger 2020 BEC MitoPathways

Abbreviations

ADP - adenosine diphosphate
ATP - adenosine triphosphate
BMR - basal metabolic rate
ce - living cells
CHNO - reduced fuel substrate
cO2 [µM] - O2 concentration
dce - dead cells
E - ET capacity
ET - electron transfer
ETS - electron transfer system
IO2 - oxygen flow
jcyt c - cytochrome c control efficiency; jcyt c = (JCHNOc-JCHNO)/JCHNOc
JO2 - oxygen flux
jE-L=(E-L)/E - ET-coupling efficiency
JV,O2 - volume-specific O2 flux, per V of the experimental chamber
J°O2 - instrumental background O2 flux
k - catabolic reaction
L - LEAK rate of respiration
M - malate
MiR05 - mitochondiral respiration medium 5
Nce [x] - cell count
N-pathway - NADH-linked pathway
NS-pathway - convergent NADH- and succinate-linked pathway
OXPHOS - oxidative phosphorylation
P - pyruvate
P - OXPHOS capacity
Pi - inorganic phosphate
pO2 [kPa] - partial oxygen pressure
R - ROUTINE respiration
Rox - residual oxygen consumption
rO2 - rate of concentration change
S - succinate
SO2 [µmol·kPa-1] - oxygen solubility
S-pathway - succinate-linked pathway
t [s] - time
V [L] - volume of the experimental chamber
vce - viable cells
νO2 - stoichiometric number of O2 in a specified transformation, such as the reaction k
ξ - advancement of a transformation


Cited by

  • Lane Nick (2022) Transformer: the deep chemistry of life and death. Profile Books:400 pp. ISBN-10: 0393651487 - »Bioblast link«
Under 'Further reading': Erich Gnaiger, Mitochondrial Pathways and Respiratory Control. An Introduction to OXPHOS Analysis (Innsbruck, Bioenergetics Communications, 2020). Available here: http://doi:10.26124/bec:2020-0002. The 'bible' of fluorespirometry, privately published by Erich Gnaiger in the tradition of Peter Mitchell's 'little grey books'; this is the little blue book. Gives practical insights into how the Krebs cycle really works. Introduces the idea of the Q junction, where electrons funnel from many substrates, including glycerol phosphate outside the mitochondria, into complex III.
  • Gnaiger E, Cardoso LHD, Tindle-Solomon L, Cocco P, eds (2022) Bioblast 2022: BEC inaugural conference. https://doi.org/10.26124/bec:2022-0001
  • Heimler SR, Phang HJ, Bergstrom J, Mahapatra G, Dozier S, Gnaiger E, Molina AJA (2021) Platelet bioenergetics are associated with resting metabolic rate and exercise capacity in older adult women. https://doi.org/10.26124/bec:2022-0002
  • Zdrazilova L, Hansikova H, Gnaiger E (2022) Comparable respiratory activity in attached and suspended human fibroblasts. https://doi.org/10.1371/journal.pone.0264496
  • Komlódi et al (2022) The protonmotive force - not merely membrane potential. MitoFit Preprints 2022 (in prep)
  • Donnelly C, Schmitt S, Cecatto C, Cardoso LHD, Komlodi T, Place N, Kayser B, Gnaiger E (2022) The ABC of hypoxia – what is the norm. https://doi.org/10.26124/mitofit:2022-0025
  • Baglivo E, Cardoso LHD, Cecatto C, Gnaiger E (2022) Statistical analysis of instrumental reproducibility as internal quality control in high-resolution respirometry. https://doi.org/10.26124/mitofit:2022-0018.v2
Gnaiger 2021 Bioenerg Commun


Gnaiger E (2021) Beyond counting papers – a mission and vision for scientific publication. Bioenerg Commun 2021.5. https://doi:10.26124/BEC:2021-0005
  • Vernerova A, Garcia-Souza LF, Soucek O, Kostal M, Rehacek V, Krcmova LK, Gnaiger E, Sobotka O (2021) Mitochondrial respiration of platelets: comparison of isolation methods. https://doi.org/10.3390/biomedicines9121859
Gnaiger E (2021) Bioenergetic cluster analysis – mitochondrial respiratory control in human fibroblasts. MitoFit Preprints 2021.8.


Gnaiger E (2021) Bioenergetic cluster analysis – mitochondrial respiratory control in human fibroblasts. MitoFit Preprints 2021.8. https://doi.org/10.26124/mitofit:2021-0008
  • Krako Jakovljevic N, Ebanks B, Katyal G, Chakrabarti L, Markovic I, Moisoi N (2021) Mitochondrial homeostasis in cellular models of Parkinson’s Disease. Bioenerg Commun 2021.2. https://doi.org/10.26124/bec:2021-0002
  • Komlódi T, Cardoso LHD, Doerrier C, Moore AL, Rich PR, Gnaiger E (2021) Coupling and pathway control of coenzyme Q redox state and respiration in isolated mitochondria. Bioenerg Commun 2021.3. https://doi.org/10.26124/bec:2021-0003
  • Cardoso et al (2021) Magnesium Green for fluorometric measurement of ATP production does not interfere with mitochondrial respiration. Bioenerg Commun 2021.1. doi:10.26124/bec:2021-0001
  • Went N, Di Marcello M, Gnaiger E (2021) Oxygen dependence of photosynthesis and light-enhanced dark respiration studied by High-Resolution PhotoRespirometry. MitoFit Prep 2021.5. - »Bioblast link«
  • Silva et al (2021) Off-target effect of etomoxir on mitochondrial Complex I. MitoFit Preprints 2021. (in preparation)
Gnaiger Erich et al ― MitoEAGLE Task Group (2020) Mitochondrial physiology. Bioenerg Commun 2020.1.
Gnaiger E et al ― MitoEAGLE Task Group (2020) Mitochondrial physiology. Bioenerg Commun 2020.1. doi:10.26124/bec:2020-0001.v1.



Labels: MiParea: Respiration, Instruments;methods, mt-Biogenesis;mt-density, Comparative MiP;environmental MiP, Exercise physiology;nutrition;life style, mt-Medicine, mt-Awareness 


Organism: Human, Mouse  Tissue;cell: Heart, Skeletal muscle, Fibroblast  Preparation: Permeabilized cells, Permeabilized tissue, Homogenate, Isolated mitochondria, Intact cells 

Regulation: Coupling efficiency;uncoupling, Flux control, mt-Membrane potential, Threshold;excess capacity, Uncoupler  Coupling state: LEAK, ROUTINE, OXPHOS, ET  Pathway: F, N, S, Gp, CIV, NS, ROX  HRR: Oxygraph-2k, O2k-Fluorometer, O2k-Protocol, Theory 

Additivity, BEC, BEC2020, MitoFitPublication, MitoEAGLEPublication, MitoPathways, O2k-chemicals and media, Mt-preparations, O2k-Demo, O2k-Core, 1R;2Omy;3U-, 1PGM;2D;3U-, 1PGM;2D;2c;3S;4U;5Rot;6Ama, 1OctM;2D;3G;4S;5U;6Rot;7Ama, Activity, Advancement, Amount of substance, Ampere, Assay, Avogadro constant, Barometric pressure, Biochemical coupling efficiency, Body mass, Boltzmann constant, Cell count and normalization in HRR, Cell respiration, Charge number, Citrate synthase activity, Closed chamber, Concentration, Count, Coupling-control ratio, Density, Dimension, Efficiency, Electric current, Electrochemical constant, Electron transfer pathway, Elementary charge, Elementary entity, Energy, Entity, ET capacity, Extensive quantity, E-L coupling efficiency, E-L net ET capacity, E-P excess capacity, E-P control efficiency, E-R reserve capacity, E-R control efficiency, Elementary charge, Faraday constant, Flow, Flux, Flux control efficiency, Flux control ratio, Force, Format, Gas constant, High-resolution respirometry, Iconic symbols, International System of Units, Isolated mitochondria, LEAK-respiration, Living cells, L/P coupling control ratio, L/R coupling control ratio, Malic enzyme, Mass, Mitochondrial marker, Mole, Motive unit, Normalization of rate, Number, Open chamber, OXPHOS capacity, OXPHOS-control ratio, Oxygen flow, Oxygen pressure, Oxygen solubility, Power, P-L net OXPHOS capacity, Pascal, Pathway control ratio, Permeabilized cells, Pressure, P-L control efficiency, Pressure, Protonmotive force, Quantities, Quantity, Reproducibility crisis, Residual oxygen consumption, Respiratory states, Respirometry, ROUTINE-control ratio, ROUTINE-coupling efficiency R-L, ROUTINE respiration, R-L net ROUTINE capacity, Sample, SI prefixes, Solubility, Solutions, Specific quantity, Symbols, System, Unit, Volume, Work, BEC 2020.1, X-mass Carol, MitoFit 2021 MgG, MitoFit 2021 CoQ, MitoFit 2021.5 PB, MitoFit 2021 BCA, MitoFit 2021 PLT, BEC2021.5, PLoSONE2022ace-sce, MitoFit2022Hypoxia, MitoFit 2022 NADH, MitoFit 2022 pmF, MitoFit2022QC 


MitoPedia topics: BEC