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Gnaiger 2023 MitoFit CII

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Gnaiger E (2023) Complex II ambiguities ā€• FADH2 in the electron transfer system. MitoFit Preprints 2023.3.v5. https://doi.org/10.26124/mitofit:2023-0003.v5

Ā» MitoFit Preprints 2023.3.v5.

MitoFit pdf

Complex II ambiguities ā€• FADH2 in the electron transfer system

Gnaiger Erich (2023) MitoFit Prep

Abstract:

CII-ambiguities Graphical abstract.png
Version 5 (v5) 2023-05-31 10.26124/mitofit:2023-0003.v5
Version 4 (v4) 2023-05-12
Version 3 (v3) 2023-05-04
Version 2 (v2) 2023-04-04
Version 1 (v1) 2023-03-24 - Ā»Link to all versionsĀ«

The prevailing notion that reduced cofactors NADH and FADH2 transfer electrons from the tricarboxylic acid cycle to the mitochondrial electron transfer system creates ambiguities regarding respiratory Complex II (CII). The succinate dehydrogenase subunit SDHA of CII oxidizes succinate and reduces the covalently bound prosthetic group FAD to FADH2 in the canonical forward tricarboxylic acid cycle. However, several graphical representations of the electron transfer system depict FADH2 in the mitochondrial matrix to be oxidized by CII. This leads to the false conclusion that FADH2 from the Ī²-oxidation cycle in fatty acid oxidation feeds electrons into CII. In reality, dehydrogenases of fatty acid oxidation channel electrons to the coenzyme Q-junction but not through CII. The ambiguities surrounding Complex II in the literature and educational resources call for quality control, to secure scientific standards in current communications of bioenergetics, and ultimately support adequate clinical applications. This review aims to raise awareness of the inherent ambiguity crisis, complementing efforts to address the well-acknowledged issues of credibility and reproducibility.
ā€¢ Keywords: coenzyme Q junction, Q-junction; Complex II, CII; electron transfer system, ETS; fatty acid oxidation, FAO; flavin adenine dinucleotide, FAD/FADH2; nicotinamide adenine dinucleotide, NAD+/NADH; succinate dehydrogenase, SDH; tricarboxylic acid cycle, TCA

ā€¢ O2k-Network Lab: AT Innsbruck Oroboros

ORCID: ORCID.png Gnaiger Erich, Oroboros Instruments, Innsbruck, Austria

The ambiguity crisis

Towards version 6 (2023-06-06)
A prominent case of the ambiguity crisis in bioenergetcs has been uniquely demonstrated by analysis of the popular notion of 'oxidative stress' - a term more frequently found in PubMed than 'mitochondria', widely used without unambiguous definition and without expression by numerical values and corresponding units (Azzi 2022). Another example for the ambiguity crisis is the use of the term and experimental application of 'hypoxia' and 'normoxia' in bioenergetics (Gnaiger et al 2000; Donnelly et al 2022), when air-level normoxic conditions for isolated mitochondria are effectively hyperoxic and may cause oxidative damage (hic! - avoiding the ambiguous term oxidative stress). Another ambiguity in bioenergetics links to the confusing use of the terms uncoupling, decoupling, dyscoupling, where rigorous definition is warranted (Gnaiger et al 2020). Linking bioenergetics to physical chemistry and the thermodynamics of irreversible processes, the ambiguous use of the terms force and pressure (vant'Hoff 1901; Einstein 1905; Nernst 1921; Prigogine 1967; Mitchell 1966) has deep consequences on the enigmatic concept of non-ohmic flux-force relationships in the context of mitochondrial membrane potential and the protonmotive force (Gnaiger 2020, Chapter 8). The present review adds Complex II ambiguities to the growing list.


N-S FADH2-FMNH2.png

Figure 1. Complex II (SDH) bridges H+-linked electron transfer from the TCA cycle (matrix-ETS) to the electron transfer system (membrane-ETS) of the mt-inner membrane (mtIM). (a) NADH+H+ and (b) succinate are substrates of 2{H++e-} transfer to CI and CII, respectively, with prosthetic groups FMN and FAD as the corresponding electron acceptors. (c) Symbolic representation of ETS pathway architecture. Electron flow converges at the N-junction (NAD+ ā†’ NADH+H+). Electron flow from NADH and succinate S converges through CI and CII at the Q-junction. CIII passes electrons to cytochrome c and in CIV to molecular O2, 2{H++e-}+0.5 O2 ā‡¢ H2O. (d) NADH+H+ and NAD+ cycle between matrix-dehydrogenases and CI, whereas FAD and FADH2 cycle permanently bound within the same enzyme CII. Succinate and fumarate indicate the chemical entities irrespective of ionization, but charges are shown in NADH, NAD+, and H+. Joint pairs of half-circular arrows distinguish electron transfer 2{H++eĀ­-} to CI and CII from vectorial H+ translocation across the mtIM (H+neg ā†’ H+pos). CI and CIII pump hydrogen ions from the negatively (neg) to the positively charged compartment (pos). (e) Iconic representation of SDH subunits. SDHA catalyzes the oxidation succinate ā†’ fumarate + 2{H++e-} and reduction FAD + 2{H++e-} ā†’ FADH2 in the soluble domain of CII. The ironā€“sulfur protein SDHB transfers electrons through Fe-S clusters to the mtIM domain where ubiquinone UQ is reduced to ubiquinol UQH2 in SDHC and SDHD.

FAO.png

Figure 4. Fatty acid oxidation through the Ī²-oxidation cycle (Ī²-ox), the multi-enzyme electron transferring flavoprotein Complex (CETF, ETF:ETFDH; see text), and Complex I (CI) with convergent electron transfer into the Q-junction.

Acknowledgements: I thank Luiza H. Cardoso and Sabine Schmitt for stimulating discussions, and Paolo Cocco for expert help on the graphical abstract and Figures 1d and e. The constructive comments of an anonymous reviewer (J Biol Chem) are explicitly acknowledged. Contribution to the European Unionā€™s Horizon 2020 research and innovation program Grant 857394 (FAT4BRAIN).

Supplement 1. Footnotes on terminology

A coenzyme or cosubstrate is a cofactor that is attached loosely and transiently to an enzyme (IUPAC definition).
A cofactor is 'an organic molecule or ion (usually a metal ion) that is required by an enzyme for its activity. It may be attached either loosely (coenzyme) or tightly (prosthetic group)' (IUPAC definition).
The convergent architecture of the electron transfer system is emphasized in contrast to linear electron transfer chains ETCs within segments of the ETS.
  • Electron transfer:
A distinction is necessary between electron transfer in redox reactions and electron transport (translocation) in the diffusion of charged ionic species within or between cellular compartments. The symbol 2{H++eāˆ’} is introduced to indicate H+-linked electron transfer of two hydrogen ions and two electrons in a redox reaction.
  • H+-linked electron transfer:
The term H+-coupled electron transfer (Hsu et al 2022) is replaced by H+-linked electron transfer, to avoid confusion with coupled H+ translocation.
  • Matrix-ETS:
Electron transfer and corresponding OXPHOS capacities are classically studied in mitochondrial preparations as oxygen consumption supported by various fuel substrates undergoing partial oxidation in the mt-matrix, such as pyruvate, malate, succinate, and others. Therefore, the matrix component of ETS (matrix-ETS) is distinguished from the ETS bound to the mt-inner membrane (membrane-ETS; Gnaiger et al 2020).
  • Membrane-ETS:
Electron transfer is frequently considered as the segment of redox reactions linked to the mtIM. However, the membrane-ETS is only part of the total ETS, which includes the upstream matrix-ETS.
  • Misinformation:
Misinformation is the mistaken sharing of the same content (Wardle 2023).
A prosthetic group is cofactor that is attached permanently and tightly or even covalently to an enzyme and that is regenerated in each enzymatic turnover.
A substrate in a chemical reaction has a negative stoichiometric number since it is consumed, whereas a product has a positive stoichiometric number since it is produced. The general definition of a substrate in an enzyme-catalized reaction relies on the definition of the chemical reaction, without restriction to the nature of the substrate, i.e. independent of the substrate being a chemical entity in solution or a loosely bound cosubstrate (coenzyme) or even a tightly bound prosthetic group. The latter may be explicitly distinguished as a bound (internal) substrate from a free (external) substrate. Even different substrate pools may coexist (CoQ).
  • 2{H++e-}
The symbol [2 H] is frequently used to indicate redox equivalents in the transfer from hydrogen donors to hydrogen acceptors. However, 2[H] does not explicitly express that it applies to both electron and hydrogen ion transfer. Brackets are avoided to exclude the confusion with their frequent application to indicate amount-of-substance concentrations. Two-electron transfer 2{H++e-} is distinguished from single-electron transfer {H+}+{e-}.


Supplement 2. FAD a substrate of SDH and FADH2 a substrate of CII

Figure S2. Complex II ambiguities in graphical representations on FADH2 as a substrate of Complex II in the canonical forward electron transfer. The TCA cycle reduces FAD to FADH2 - in several cases shown to be catalyzed by SDH. Then FADH2 is erroneously shown to feed electrons into CII. Alphabetical sequence of publications from 2001 to 2023.


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Supplement 3. FADH2 a substrate of CII

Figure S3. Complex II ambiguities in graphical representations on FADH2 as a substrate of Complex II in the canonical forward electron transfer. Alphabetical sequence of publications from 2001 to 2023.
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Supplement 4. FADH2 as substrate of CII and FAD + 2H+ as products

Figure S4. Complex II ambiguities: FADH2 as substrate of CII and FAD + 2H+ as products. Alphabetical sequence of publications from 2001 to 2023.
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a Ahmad M, Wolberg A, Kahwaji CI (2022) Biochemistry, electron transport chain. StatPearls Publishing StatPearls [Internet]. Treasure Island (FL) - Ā»Bioblast linkĀ«


Chen 2022 Int J Mol Sci CORRECTION.png
b Chen TH, Koh KY, Lin KM, Chou CK (2022) Mitochondrial dysfunction as an underlying cause of skeletal muscle disorders. Int J Mol Sci 23:12926. - Ā»Bioblast linkĀ«


El-Gammal 2022 Pflugers Arch CORRECTION.png
c El-Gammal Z, Nasr MA, Elmehrath AO, Salah RA, Saad SM, El-Badri N (2022) Regulation of mitochondrial temperature in health and disease. Pflugers Arch 474:1043-51. - Ā»Bioblast linkĀ«


Hidalgo-Gutierrez CORRECTION.png
d Hidalgo-GutiĆ©rrez A, GonzĆ”lez-GarcĆ­a P, DĆ­az-Casado ME, Barriocanal-Casado E, LĆ³pez-Herrador S, Quinzii CM, LĆ³pez LC (2021) Metabolic targets of coenzyme Q10 in mitochondria. Antioxidants (Basel) 10:520. - Ā»Bioblast linkĀ«


Payen 2019 Cancer Metastasis Rev CORRECTION.png
e Payen VL, Zampieri LX, Porporato PE, Sonveaux P (2019) Pro- and antitumor effects of mitochondrial reactive oxygen species. Cancer Metastasis Rev 38:189-203. - Ā»Bioblast linkĀ«


Prasuhn 2021 Front Cell Dev Biol CORRECTION.png
f Prasuhn J, Davis RL, Kumar KR (2021) Targeting mitochondrial impairment in Parkinson's disease: challenges and opportunities. Front Cell Dev Biol 8:615461. - Ā»Bioblast linkĀ«


Tseng 2022 Cells CORRECTION.png
g Tseng W-W, Wei A-C (2022) Kinetic mathematical modeling of oxidative phosphorylation in cardiomyocyte mitochondria. Cells 11:4020. - Ā»Bioblast linkĀ«


Turton 2021 Expert Opinion Orphan Drugs CORRECTION.png
h Turton N, Bowers N, Khajeh S, Hargreaves IP, Heaton RA (2021) Coenzyme Q10 and the exclusive club of diseases that show a limited response to treatment. Expert Opinion Orphan Drugs 9:151-60. - Ā»Bioblast linkĀ«


Yin 2021 FASEB J CORRECTION.png
i Yin M, O'Neill LAJ (2021) The role of the electron transport chain in immunity. FASEB J 35:e21974. - Ā»Bioblast linkĀ«


Supplement 5. FADH2 as substrate of CII and FAD+ as product

Figure S5. Complex II ambiguities: FADH2 as substrate of CII and FAD+ as products. Alphabetical sequence of publications from 2001 to 2023.
Area-Gomez 2019 J Clin Invest CORRECTED.png
a Area-Gomez E, Guardia-Laguarta C, Schon EA, Przedborski S (2019) Mitochondria, OxPhos, and neurodegeneration: cells are not just running out of gas. J Clin Invest 129:34-45. - Ā»Bioblast linkĀ«


Carriere 2019 Academic Press CORRECTION.png
b Carriere A, Casteilla L (2019) Role of mitochondria in adipose tissues metabolism and plasticity. Academic Press In: Mitochondria in obesity and type 2 diabetes. Morio B, PĆ©nicaud L, Rigoulet M (eds) Academic Press. - Ā»Bioblast linkĀ«


Fisher-Wellman 2012 Trends Endocrinol Metab Fig2 CORRECTION.png
c, d Fisher-Wellman KH, Neufer PD (2012) Linking mitochondrial bioenergetics to insulin resistance via redox biology. Trends Endocrinol Metab 23:142-53. - Ā»Bioblast linkĀ«


Gero 2018 IntechOpen CORRECTION.png
e Gero D (2023) Hyperglycemia-induced endothelial dysfunction. IntechOpen Chapter 8. - Ā»Bioblast linkĀ«


Onukwufor 2022 Antioxidants (Basel) CORRECTION.png
f Onukwufor JO, Dirksen RT, Wojtovich AP (2022) Iron dysregulation in mitochondrial dysfunction and Alzheimer's disease. Antioxidants (Basel) 11:692. - Ā»Bioblast linkĀ«


Shirakawa 2023 Sci Rep CORRECTION.png
g Shirakawa R, Nakajima T, Yoshimura A, Kawahara Y, Orito C, Yamane M, Handa H, Takada S, Furihata T, Fukushima A, Ishimori N, Nakagawa M, Yokota I, Sabe H, Hashino S, Kinugawa S, Yokota T (2023) Enhanced mitochondrial oxidative metabolism in peripheral blood mononuclear cells is associated with fatty liver in obese young adults. Sci Rep 13:5203. - Ā»Bioblast linkĀ«
While CI functions as a proton pump, CII does not. Depicting CII as a proton pump would be analogous to falsely portraying FADH2 as the substrate of CII, as if it were a copy of CI, which functions as a proton pump with NADH as its substrate.


Sullivan 2014 Cell Cycle CORRECTION.png
h Sullivan LB, Chandel NS (2014) Mitochondrial metabolism in TCA cycle mutant cancer cells. Cell Cycle 13:347-8. - Ā»Bioblast linkĀ«


Valle-Mendiola 2020 Cancers (Basel) CORRECTION.png
i Valle-Mendiola A, Soto-Cruz I (2020) Energy metabolism in cancer: The roles of STAT3 and STAT5 in the regulation of metabolism-related genes. Cancers (Basel) 12:124. - Ā»Bioblast linkĀ«




Supplement 6. FADH2 or FADH as substrate of CII and FADH, FADH+, or FAD+ as product

Figure S6. Complex II ambiguities: FADH2 as substrate of CII and FADH or FADH+ as product. Sequence of publications from 2001 to 2023 according to (4) to (9).
Cadonic 2016 Mol Neurobiol CORRECTION.png
a Cadonic C, Sabbir MG, Albensi BC (2016) Mechanisms of mitochondrial dysfunction in Alzheimer's disease. Mol Neurobiol 53:6078-90. - Ā»Bioblast linkĀ«


Kezic 2016 Oxid Med Cell Longev CORRECTION.png
b Kezic A, Spasojevic I, Lezaic V, Bajcetic M (2016) Mitochondria-targeted antioxidants: future perspectives in kidney ischemia reperfusion injury. Oxid Med Cell Longev 2016:2950503. - Ā»Bioblast linkĀ«


Li 2013 J Hematol Oncol CORRECTION.png
c Li X, Fang P, Mai J, Choi ET, Wang H, Yang XF (2013) Targeting mitochondrial reactive oxygen species as novel therapy for inflammatory diseases and cancers. J Hematol Oncol 6:19. - Ā»Bioblast linkĀ«


Yang 2020 Transl Neurodegener CORRECTION.png
d Yang L, Youngblood H, Wu C, Zhang Q (2020) Mitochondria as a target for neuroprotection: role of methylene blue and photobiomodulation. Transl Neurodegener 9:19. - Ā»Bioblast linkĀ«


Torres 2017 Cell Metab CORRECTION.png
e Torres MJ, Kew KA, Ryan TE, Pennington ER, Lin CT, Buddo KA, Fix AM, Smith CA, Gilliam LA, Karvinen S, Lowe DA, Spangenburg EE, Zeczycki TN, Shaikh SR, Neufer PD (2018) 17Ī²-estradiol directly lowers mitochondrial membrane microviscosity and improves bioenergetic function in skeletal muscle. Cell Metab 27:167-79. - Ā»Bioblast linkĀ«


Johnson 2013 Eukaryot Cell CORRECTION.png
f Johnson X, Alric J (2013) Central carbon metabolism and electron transport in Chlamydomonas reinhardtii: metabolic constraints for carbon partitioning between oil and starch. Eukaryot Cell 12:776-93. - Ā»Bioblast linkĀ«


Middleton 2021 Therap Adv CORRECTION.png
g Middleton P, Vergis N (2021) Mitochondrial dysfunction and liver disease: role, relevance, and potential for therapeutic modulation. Therap Adv Gastroenterol 14:17562848211031394. - Ā»Bioblast linkĀ«


Puntel 2013 Toxicol In Vitro CORRECTION.png
h Puntel RL, Roos DH, Seeger RL, Rocha JB (2013) Mitochondrial electron transfer chain complexes inhibition by different organochalcogens. Toxicol In Vitro 27:59-70. - Ā»Bioblast linkĀ«


Xing 2022 Atlantis Press CORRECTION.png
i Xing Yunxie (2022) Is genome instability a significant cause of aging? A review. Atlantis Press. - Ā»Bioblast linkĀ«



Supplement 7. FADH2 or FADH as substrate of CII in websites

Figure S7. Complex II ambiguities in graphical representations on FADH2 as a substrate of Complex II in the canonical forward electron transfer. FADH ā†’ FAD+H (g), FADH2 ā†’ FAD+2H+ (aā€™, c, h-n), and FADH2 ā†’ FAD (a, b, d-f, o-Īø) should be corrected to FADH2 ā†’ FAD (Eq. 3b). NADH ā†’ NAD+ is frequently written in graphs without showing the H+ on the left side of the arrow, except for (p-r). NADH ā†’ NAD++H+ (a-g, m), NADH ā†’ NAD++2H+ (h-l), NADH+H+ ā†’ NAD++2H+ (j, k), and NADH ā†’ NAD (Ī¹) should be corrected to NADH+H+ ā†’ NAD+ (Eq. 3a). (Retrieved 2023-03-21 to 2023-05-04).
OpenStax Biology.png
(a)
Website 1 (a,b): OpenStax Biology - Fig. 7.10 Oxidative phosphorylation (CC BY 3.0). - OpenStax Biology got it wrong in figures and text. The error is copied without quality assessment and propagated in several links.
Website 2 (a,b): Concepts of Biology - 1st Canadian Edition by Charles Molnar and Jane Gair - Fig. 4.19a
Website 3 (a,b): Pharmaguideline
Website 4 (a,b): Texas Gateway - Figure 7.11
Website 5 (a,b): - CUNY
Website 6 (a,b): lumen Biology for Majors I - Fig. 1
Website 7 (a): LibreTexts Biology Oxidative Phosphorylation - Electron Transport Chain - Figure 7.11.1
Website 8 (a): - Brain Brooder
Khan Academy modified from OpenStax CORRECTION.png
(aā€™)
Website 9 (aā€™,b,v): Khan Academy - Image modified from "Oxidative phosphorylation: Figure 1", by OpenStax College, Biology (CC BY 3.0). Figure and text underscore the FADH2-error: "FADH2 .. feeds them (electrons) into the transport chain through complex II."
Website 10 (aā€™,b,v): Saylor Academy
Expii OpenStax CORRECTION.png
(b)
Website 1 (a,b): OpenStax Biology - Fig. 7.12
Website 2 (a,b): Concepts of Biology - 1st Canadian Edition by Charles Molnar and Jane Gair - Fig. 4.19c
Website 3 (a,b): Pharmaguideline
Website 4 (a,b): Texas Gateway - Figure 7.13
Website 5 (a,b): - CUNY
Website 6 (a,b): lumen Biology for Majors I - Fig. 3
Website 9 (aā€™,b,v): Khan Academy - Image modified from "Oxidative phosphorylation: Figure 3," by Openstax College, Biology (CC BY 3.0)
Website 10 (aā€™,b,v): Saylor Academy
Website 11 (b,c,n,w,Ī²): expii - Image source: By CNX OpenStax
Biologydictionary.net CORRECTION.png
(c)
Website 11 (b,c,n,w,Ī²): expii - Image source: By CNX OpenStax
Website 12 (c,t): ThoughtCo - extender01 / iStock / Getty Images Plus
Website 13 (c): wikimedia 30148497 - Anatomy & Physiology, Connexions Web site. http://cnx.org/content/col11496/1.6/, 2013-06-19
Website 14 (c): biologydictionary.net 2018-08-21
Website 15 (c): Quora
Website 16 (c): TeachMePhysiology - Fig. 1. 2023-03-13
Website 17 (c): toppr
Labxchange CORRECTION.png
(d)
Website 18 (d): Labxchange - Figure 8.15 credit: modification of work by Klaus Hoffmeier
Jack Westin CORRECTION.png
(e)
Website 19 (e): Jack Westin MCAT Courses
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Website 20 (f): videodelivery
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Website 21 (g): - SparkNotes
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Website 22 (h,t): researchtweet
Website 23 (h): Microbe Notes
FlexBooks 2 0 CORRECTION.png
(i)
Website 24 (i): FlexBooks - CK-12 Biology for High School- 2.28 Electron Transport, Figure 2
Labster Theory CORRECTION.png
(j)
Website 25 (j): Labster Theory
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(k)
Website 26 (k): nau.edu
ScienceFacts CORRECTION.png
(l)
Website 27 (l): ScienceFacts
Ck12 CORRECTION.png
(m)
Website 28 (m): cK-12
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(n)
Website 11 (b,c,n,w,Ī²): expii - Image source: By CNX OpenStax
Website 29 (n): Wikimedia
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(o)
Website 30 (o): creative-biolabs
Vector Mine CORRECTION.png
(p)
Website 31 (p): dreamstime
Website 32 (p): VectorMine
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(q)
Website 33: YouTube Dirty Medicine Biochemistry - Uploaded 2019-07-18
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(r)
Website 34 (r): DBriers
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(s)
Website 35 (s): SNC1D - BIOLOGY LESSON PLAN BLOG
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(t)
Website 12 (c,t): ThoughtCo - extender01 / iStock / Getty Images Plus
Website 22 (h,t): researchtweet
Website 36 (t): dreamstime
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(u)
Website 37 (u): hyperphysics
Khan Academy CORRECTION.png
(v)
Website 9 (aā€™,b,v): Khan Academy
Website 10 (aā€™,b,v): Saylor Academy
Expii-Whitney, Rolfes 2002 CORRECTION.png
(w)
Website 11 (b,c,n,w,Ī²): expii - Whitney, Rolfes 2002
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(x)
Website 38 (x): UrbanPro
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(y)
Website 39 (y): Quizlet
Unm.edu CORRECTION.png
(z)
Website 40 (z): unm.edu
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(Ī±)
Website 41 (Ī±): YouTube sciencemusicvideos - Uploaded 2014-08-19
Expii-Gabi Slizewska CORRECTION.png
(Ī²)
Website 11 (b,c,n,w,Ī²): expii expii - Image source: By Gabi Slizewska
BiochemDen CORRECTION.png
(Ī³)
Website 42 (Ī³): BiochemDen.com
Hopes CORRECTION.png
(Ī“)
Website 43 (Ī“): hopes, Huntingtonā€™s outreach project for education, at Stanford
Studocu CORRECTION.png
(Īµ)
Website 44 (Īµ): [ https://www.studocu.com/en-gb/document/university-college-london/mammalian-physiology/electron-transport-chain/38063777 studocu, University College London]
ScienceDirect CORRECTION.png
(Ī¶)
Website 45 (Ī¶): ScienceDirect
BBC BITESIZE CORRECTION.png
(Ī·)
Website 46 (Ī·): BBC BITESIZE cK-12
Freepik CORRECTION.png
(Īø)
Website 47 (Īø): freepik
LibreTexts Chemistry CORRECTION.png
(Ī¹)
Website 48 (Ī¹): - LibreTexts Chemistry - The Citric Acid Cycle and Electron Transport ā€“ Fig. 12.4.3


Supplement 8. Weblinks on FAO and CII

(retrieved 2023-03-21 to 2023-05-02)
Website 49: Conduct Science: "In Complex II, the enzyme succinate dehydrogenase in the inner mitochondrial membrane reduce FADH2 to FAD+. Simultaneously, succinate, an intermediate in the Krebs cycle, is oxidized to fumarate." - Comments: FAD does not have a postive charge. FADH2 is the reduced form, it is not reduced. And again: In CII, FAD is reduced to FADH2.
Website 50: The Medical Biochemistry Page: ā€˜In addition to transferring electrons from the FADH2 generated by SDH, complex II also accepts electrons from the FADH2 generated during fatty acid oxidation via the fatty acyl-CoA dehydrogenases and from mitochondrial glycerol-3-phosphate dehydrogenase (GPD2) of the glycerol phosphate shuttleā€™ (Figure 8d).
Website 51: CHM333 LECTURES 37 & 38: 4/27 ā€“ 29/13 SPRING 2013 Professor Christine Hrycyna: Acyl-CoA dehydrogenase is listed under 'Electron transfer in Complex II'.


Supplement 9. CII as a proton pump

Figure S9. Complex II as a proton pump
Cronshaw 2019 Photobiomodul Photomed Laser Surg CORRECTION.png
a Cronshaw M, Parker S, Arany P (2019) Feeling the heat: evolutionary and microbial basis for the analgesic mechanisms of photobiomodulation therapy. Photobiomodul Photomed Laser Surg 37:517-26. - Ā»Bioblast linkĀ«


Jian 2020 Cell Metab CORRECTION.png
b Jian C, Fu J, Cheng X, Shen LJ, Ji YX, Wang X, Pan S, Tian H, Tian S, Liao R, Song K, Wang HP, Zhang X, Wang Y, Huang Z, She ZG, Zhang XJ, Zhu L, Li H (2020) Low-dose sorafenib acts as a mitochondrial uncoupler and ameliorates nonalcoholic steatohepatitis. Cell Metab 31:892-908. - Ā»Bioblast linkĀ«
While CI functions as a proton pump, CII does not. Depicting CII as a proton pump would be analogous to falsely portraying FADH2 as the substrate of CII, as if it were a copy of CI, which functions as a proton pump with NADH as its substrate.


Shirakawa 2023 Sci Rep CORRECTION.png
c Shirakawa R, Nakajima T, Yoshimura A, Kawahara Y, Orito C, Yamane M, Handa H, Takada S, Furihata T, Fukushima A, Ishimori N, Nakagawa M, Yokota I, Sabe H, Hashino S, Kinugawa S, Yokota T (2023) Enhanced mitochondrial oxidative metabolism in peripheral blood mononuclear cells is associated with fatty liver in obese young adults. Sci Rep 13:5203. - Ā»Bioblast linkĀ«
While CI functions as a proton pump, CII does not. Depicting CII as a proton pump would be analogous to falsely portraying FADH2 as the substrate of CII, as if it were a copy of CI, which functions as a proton pump with NADH as its substrate.


Expii-Gabi Slizewska CORRECTION.png
d: expii expii - Image source: By Gabi Slizewska: ā€˜FADH2 from glycolysis and Krebs cycle is oxidized to FAD by Complex II. It also releases H+ ions into the intermembrane space and passes off electronsā€™ (retrieved 2023-05-04).
BioNinja 1 CORRECTION.png
BioNinja 2 CORRECTION.png
e,f: BioNinja (retrieved 2023-05-04).


Beyond preprint

Last update: 2023-05-21
Grandoch 2019 Nat Metab CORRECTION.png
1 Grandoch M, Flƶgel U, Virtue S, Maier JK, Jelenik T, Kohlmorgen C, Feldmann K, Ostendorf Y, CastaƱeda TR, Zhou Z, Yamaguchi Y, Nascimento EBM, Sunkari VG, Goy C, Kinzig M, Sƶrgel F, Bollyky PL, Schrauwen P, Al-Hasani H, Roden M, Keipert S, Vidal-Puig A, Jastroch M5, Haendeler J, Fischer JW (2019) 4-Methylumbelliferone improves the thermogenic capacity of brown adipose tissue. Nat Metab 1:546-59. - Ā»Bioblast linkĀ«
NADH is shown as the product of the reaction catalyzed by CI in respiration. This error is rare in the literature, but comparable to the error frequenty encountered when FADH2 is shown as the substrate of CII.


Lancaster 2002 Biochim Biophys Acta.png Lancaster 2001 FEBS Lett CORRECTION.png
2 Lancaster CR (2002) Succinate:quinone oxidoreductases: an overview. Biochim Biophys Acta 1553:1-6. - Ā»Bioblast linkĀ«
fumarate + 2H+ shown besides NADH + H+ is ambiguous.
3 Lancaster CR (2001) Succinate:quinone oxidoreductases--what can we learn from Wolinella succinogenes quinol:fumarate reductase?. FEBS Lett 504:133-41. - Ā»Bioblast linkĀ«




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Enzyme: Complex II;succinate dehydrogenase 



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