Hypoxia (hypox) is defined in respiratory physiology as the state when insufficient O2 is available for respiration, compared to environmental hypoxia defined as environmental oxygen pressures below the normoxic reference level. Three major categories of hypoxia are (1) environmental hypoxia, (2) physiological tissue hypoxia in hyperactivated states (e.g. at VO2max) with intracellular oxygen demand/supply balance at steady state in tissues at environmental normoxia, compared to tissue normoxia in physiologically balanced states, and (3) pathological tissue hypoxia including ischemia and stroke, anaemia, chronic heart disease, chronic obstructive pulmonary disease, severe COVID-19, and obstructive sleep apnea. Pathological hypoxia leads to tissue hypoxia and heterogenous intracellular anoxia. Clinical oxygen treatment ('environmental hyperoxia') may not or only partially overcome pathological tissue hypoxia.
Communicated by Gnaiger E (2014-05-29) edited 2021-11-11
Aerobic and anaerobic from normoxia to anoxia: oxygen availability and metabolic state or rate
- Normoxia - "Mitochondrial p50 values are 5 to 20 times less than the half-saturation point of myoglobin, which then suggests that mitochondrial respiration operates at the edge of oxygen limitation under normoxic intracellular oxygen pressures" . "Compared with ambient oxygen pessure of 20 kPa (150 mmHg), oxygen levels are low within active tissues and are under tight control by microcirculatory adjustments to match oxygen supply and demand. Alveolar normoxia of 13 kPa (100 mmHg) contrasts with a corresponding 1 to 5 kPa (10 to 40 mmHg) extracellular pO2 in solid organs such as heart, brain, kidney and liver" . "Even in comparative physiology, the traditional perspective on transitions to anoxia is dominated by an anthropomorphic or "anthropophysiologic" recognition which centers around the normoxic condition. We are aerobically poised and view the world from the preferred normoxic environment" . "It remains to be defined, how low the pO2 needs to be set in the incubation medium to provide a “normoxic” environment for embryonic cardiomyocytes" .
- Hyperoxia - Hyperoxic conditions may impose oxidative stress and may increase maximum aerobic performance. "In the intracellular microenvironment, mitochondria are well separated from air-level oxygen pressure, and high rates of oxidative phosphorylation must be maintained near or at limiting oxygen levels in some tissues. On the other hand, mitochondria are routinely isolated and studied at unphysiologically high oxygen concentrations with limited additions of antioxidants, despite the fact that mitochondria in tissues are protected from oxidative stress by both low oxygen levels and complex defence systems against reactive oxygen species" .
- Hypoxia - "Metabolic hypoxia is indicated as a reduced oxygen flux below the critical oxygen pressure and is either fully or partially anaerobic" . Metabolism under hypoxia may be fully aerobic even below the critical oxygen pressure pc and becomes partially or fully anaerobic below the limiting oxygen pressure pl . This functional or physiological definition of hypoxia is compared to environmental hypoxia defined as environmental oxygen pressures below the normoxic reference level. "The high efficiency of oxidative phosphorylation at low oxygen emphasizes that even trace amounts of oxygen can make a vital energetic contribution when ATP limitation threatens cellular survival under severe hypoxia encountered at high altitude, in aquatic habitats, and during pathological states of ischemia" . — "O2 limitation (due to environmental hypoxia, tissue-work-related hypoxia, or tissue ischemia)" 
- Microxia - "Microxic regulation .. effectively increases the slope of the flux-pressure relation in the microxic region" . "The pattern of microxic regulation is characterized by a steep oxygen flux/pressure slope at very low oxygen, despite some degree of conformation at mild hypoxia .
- Anoxia - "When strictly anoxic conditions are not achieved, anaerobic metabolism proceeds simultaneously with oxygen consumption" . "The difficulties involved in defining an absolute limit between microxic and anoxic conditions are best illustrated by a logarithmic pO2 scale . "The terms anoxic and microxic should be rigorously applied to conditions characterized by actual oxygen measurements, with reference to the sensitivity limit of the method for oxygen detection or to the tested limits of the respective oxygen removal technique" .
- Aerobic - Whereas anaerobic metabolism may proceed in the absence or presence of oxygen (anoxic or oxic conditions), aerobic metabolism is restricted to oxic conditions.
- Anaerobic - "In zoophysiology, 'anaerobic' (without air) is rarely defined in terms of controlled measurements of the actual extent of anaerobic conditions . "In contrast to the aerobically balanced metabolism of animals, tissues and harvested cells under normoxic and a wide range of hypoxic states, many cultured cells are frequently below the limiting pO2 under standard aerobic culture conditions, incurring simultaneous aerobic and anaerobic metabolism" . "Two disparate features characterize animal anaerobiosis: high power output in the case of physiologically induced hypoxia, and high efficiency of energy conversion under environmental anoxia . Terms shown in italics have been updated for consistency of nomenclature.
Critical and limiting pO2
- Critical oxygen pressure - "Metabolic hypoxia is indicated as a reduced oxygen flux below the critical oxygen pressure .
- Limiting oxygen pressure - "Below the critical oxygen pressure, the aerobic ATP production decreases, and below the limiting oxygen pressure anaerobic processes compensate increasingly for the diminished aerobic flux." Then "there is an extended phase of fully aerobic hypoxia" .
- Gnaiger E (1983) Heat dissipation and energetic efficiency in animal anoxibiosis. Economy contra power. J Exp Zool 228:471-90. - »Bioblast link«
- Gnaiger E (1991) Animal energetics at very low oxygen: Information from calorimetry and respirometry. In: Strategies for gas exchange and metabolism. Woakes R, Grieshaber M, Bridges CR (eds), Soc Exp Biol Seminar Series 44, Cambridge Univ Press, London:149-71. - »Bioblast link«
- Gnaiger E (1993) Homeostatic and microxic regulation of respiration in transitions to anaerobic metabolism. In: The vertebrate gas transport cascade: Adaptations to environment and mode of life. Bicudo JEPW (ed), CRC Press, Boca Raton, Ann Arbor, London, Tokyo:358-70. - »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. - »Bioblast link«
- Gnaiger E (2003) Oxygen conformance of cellular respiration. A perspective of mitochondrial physiology. Adv Exp Med Biol 543:39-55. - »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. - »Bioblast link«
- Hochachka PW, Somero GN (2002) Biochemical adaptation: mechanism and process in physiological evolution. Oxford Univ Press, New York: 466 pp. - »Bioblast link«
- Gnaiger E, Staudigl I (1987) Aerobic metabolism and physiological responses of aquatic oligochaetes to environmental anoxia. Heat dissipation, oxygen consumption, feeding and defecation. Physiol Zool 60:659-77. - »Bioblast link«
Keywords: Oxia terms
- Bioblast links: Hypoxia, normoxia, hyperoxia - >>>>>>> - Click on [Expand] or [Collapse] - >>>>>>>
|Aerobic||ox||The aerobic state of metabolism is defined by the presence of oxygen (air) and therefore the potential for oxidative reactions (ox) to proceed, particularly in oxidative phosphorylation (OXPHOS). Aerobic metabolism (with involvement of oxygen) is contrasted with anaerobic metabolism (without involvement of oxygen): Whereas anaerobic metabolism may proceed in the absence or presence of oxygen (anoxic or oxic conditions), aerobic metabolism is restricted to oxic conditions. Below the critical oxygen pressure, aerobic ATP production decreases.|
|Anaerobic||Anaerobic metabolism takes place without the use of molecular oxygen, in contrast to aerobic metabolism. The capacity for energy assimilation and growth under anoxic conditions is the ultimate criterion for facultative anaerobiosis. Anaerobic metabolism may proceed not only under anoxic conditions or states, but also under hyperoxic and normoxic conditions (aerobic glycolysis), and under hypoxic and microxic conditions below the limiting oxygen pressure.|
|Anoxia||anox||Ideally the terms anoxia and anoxic (anox, without oxygen) should be restricted to conditions where molecular oxygen is strictly absent. Practically, effective anoxia is obtained when a further decrease of experimental oxygen levels does not elicit any physiological or biochemical response. The practical definition, therefore, depends on (i) the techiques applied for oxygen removal and minimizing oxygen diffusion into the experimental system, (ii) the sensitivity and limit of detection of analytical methods of measuring oxygen (O2 concentration in the nM range), and (iii) the types of diagnostic tests applied to evaluate effects of trace amounts of oxygen on physiological and biochemical processes. The difficulties involved in defining an absolute limit between anoxic and microxic conditions are best illustrated by a logarithmic scale of oxygen pressure or oxygen concentration. In the anoxic state (State 5), any aerobic type of metabolism cannot take place, whereas anaerobic metabolism may proceed under oxic or anoxic conditions.|
|Critical oxygen pressure||pc||The critical oxygen pressure, pc, is defined as the partial oxygen pressure, pO2, below which aerobic catabolism (respiration or oxygen consumption) declines significantly. If anaerobic catabolism is activated simultaneously to compensate for lower aerobic ATP generation, then the limiting oxygen pressure, pl, is equal to the pc. In many cases, however, the pl is substantially lower than the pc.|
|Hyperoxia||hyperox||Hyperoxia is defined as environmental oxygen pressure above the normoxic reference level. Cellular and intracellular hyperoxia is imposed on isolated cells and isolated mitochondria at air-level oxygen pressures which are higher compared to cellular and intracellular oxygen pressures under tissue conditions in vivo. Hyperoxic conditions may impose oxidative stress and may increase maximum aerobic performance.|
|Hypoxia||hypox||Hypoxia (hypox) is defined in respiratory physiology as the state when insufficient O2 is available for respiration, compared to environmental hypoxia defined as environmental oxygen pressures below the normoxic reference level. Three major categories of hypoxia are (1) environmental hypoxia, (2) physiological tissue hypoxia in hyperactivated states (e.g. at VO2max) with intracellular oxygen demand/supply balance at steady state in tissues at environmental normoxia, compared to tissue normoxia in physiologically balanced states, and (3) pathological tissue hypoxia including ischemia and stroke, anaemia, chronic heart disease, chronic obstructive pulmonary disease, severe COVID-19, and obstructive sleep apnea. Pathological hypoxia leads to tissue hypoxia and heterogenous intracellular anoxia. Clinical oxygen treatment ('environmental hyperoxia') may not or only partially overcome pathological tissue hypoxia.|
|Intracellular oxygen||pO2,i||Physiological, intracellular oxygen pressure is significantly lower than air saturation under normoxia, hence respiratory measurements carried out at air saturation are effectively hyperoxic for cultured cells and isolated mitochondria.|
|Limiting oxygen pressure||pl||The limiting oxygen pressure, pl, is defined as the partial oxygen pressure, pO2, below which anaerobic catabolism is activated to contribute to total ATP generation. The limiting oxygen pressure, pl, may be substantially lower than the critical oxygen pressure, pc, below which aerobic catabolism (respiration or oxygen consumption) declines significantly.|
|Microxia||microx||Microxia (deep hypoxia) is obtained when trace amounts of O2 exert a stimulatory effect on respiration above the level where metabolism is switched to a purely anaerobic mode.|
|Normoxia||normox||hypoxic compared to tissue normoxia when grown in ambient normoxia (95 % air and 5 % CO2) and a high layer of culture medium causing oxygen diffusion limitation at high respiratory activity, but pericellular pO2 may be effectively hyperoxic in cells with low respiratory rate with a thin layer of culture medium (<2 mm). Intracellular oxygen levels in well-stirred suspended small cells (5 - 7 mm diameter; endothelial cells, fibroblasts) are close to ambient pO2 of the incubation medium, such that matching the experimental intracellular pO2 to the level of intracellular tissue normoxia requires lowering the ambient pO2 of the medium to avoid hyperoxia.|
Publications: Tissue normoxia
|MitoEAGLE 2022 MitoFit Hypoxia||2022||MitoEAGLE Hypoxia Task Group (2022) The ABC of hypoxia – what is the norm. MitoFit Preprints (in prep).||Oxidative stress;RONS|
|DiProspero 2021 Toxicol In Vitro||2021||DiProspero TJ, Dalrymple E, Lockett MR (2021) Physiologically relevant oxygen tensions differentially regulate hepatotoxic responses in HepG2 cells. Toxicol In Vitro 74:105156. doi: 10.1016/j.tiv.2021.105156||Liver||Intact cells||Hypoxia|
|Stepanova 2020 Methods Cell Biol||2020||Stepanova A, Galkin A (2020) Measurement of mitochondrial H2O2 production under varying O2 tensions. Methods Cell Biol 155:273-93.||Mouse||Nervous system||Isolated mitochondria||Oxidative stress;RONS|
|Ast 2019 Nat Metab||2019||Ast T, Mootha VK (2019) Oxygen and mammalian cell culture: are we repeating the experiment of Dr. Ox? Nat Metab 1:858-860.|
|Keeley 2019 Physiol Rev||2019||Keeley TP, Mann GE (2019) Defining physiological normoxia for improved translation of cell physiology to animal models and humans. Physiol Rev 99:161-234.|
|Stepanova 2018 J Neurochem||2018||Stepanova A, Konrad C, Manfredi G, Springett R, Ten V, Galkin A (2018) The dependence of brain mitochondria reactive oxygen species production on oxygen level is linear, except when inhibited by antimycin A. J Neurochem 148:731-45.||Mouse||Nervous system||Isolated mitochondria||Ischemia-reperfusion|
|Stuart 2018 Oxid Med Cell Longev||2018||Stuart JA, Fonseca JF, Moradi F, Cunningham C, Seliman B, Worsfold CR, Dolan S, Abando J, Maddalena LA (2018) How Supraphysiological Oxygen Levels in Standard Cell Culture Affect Oxygen-Consuming Reactions. Oxid Med Cell Longev 2018:8238459.|
|Stepanova 2018 J Cereb Blood Flow Metab||2018||Stepanova A, Konrad C, Guerrero-Castillo S, Manfredi G, Vannucci S, Arnold S, Galkin A (2018) Deactivation of mitochondrial complex I after hypoxia-ischemia in the immature brain. J Cereb Blood Flow Metab 39:1790-802.||Rat||Nervous system||Isolated mitochondria||Hypoxia|
|Stepanova 2017 J Cereb Blood Flow Metab||2017||Stepanova A, Kahl A, Konrad C, Ten V, Starkov AS, Galkin A (2017) Reverse electron transfer results in a loss of flavin from mitochondrial complex I: Potential mechanism for brain ischemia-reperfusion injury. J Cereb Blood Flow Metab 37:3649-58.||Mouse||Nervous system||Isolated mitochondria||Ischemia-reperfusion|
|Harrison 2015 J Appl Physiol||2015||Harrison DK, Fasching M, Fontana-Ayoub M, Gnaiger E (2015) Cytochrome redox states and respiratory control in mouse and beef heart mitochondria at steady-state levels of hypoxia. J Appl Physiol 119:1210-8. https://doi.org/10.1152/japplphysiol.00146.2015||Mouse|
|Carreau 2011 J Cell Mol Med||2011||Carreau A, El Hafny-Rahbi B, Matejuk A, Grillon C, Kieda C (2011) Why is the partial oxygen pressure of human tissues a crucial parameter? Small molecules and hypoxia. J Cell Mol Med 15:1239-53. doi:10.1111/j.1582-4934.2011.01258.x.|
|Richardson 2006 J Physiol||2006||Richardson RS, Duteil S, Wary C, Wray DW, Hoff J, Carlier PG (2006) Human skeletal muscle intracellular oxygenation: the impact of ambient oxygen availability. J Physiol 571:415-24. doi: 10.1113/jphysiol.2005.102327||Human||Skeletal muscle||Hypoxia|
|Pettersen 2005 Cell Prolif||2005||Pettersen EO, Larsen LH, Ramsing NB, Ebbesen P (2005) Pericellular oxygen depletion during ordinary tissue culturing, measured with oxygen microsensors. Cell Prolif 38:257-67.|
|Gnaiger 2003 Adv Exp Med Biol||2003||Gnaiger E (2003) Oxygen conformance of cellular respiration. A perspective of mitochondrial physiology. Adv Exp Med Biol 543:39-55.||Human|
|Gnaiger 2001 Respir Physiol||2001||Gnaiger E (2001) Bioenergetics at low oxygen: dependence of respiration and phosphorylation on oxygen and adenosine diphosphate supply. https://doi.org/10.1016/S0034-5687(01)00307-3||Human|
|Gnaiger 2000 Proc Natl Acad Sci U S A||2000||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.||Rat|
|Gnaiger 1998 Biochim Biophys Acta||1998||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.||Rat||Heart|
|Gnaiger 1998 J Exp Biol||1998||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.||Human|
|Gnaiger 1995 J Bioenerg Biomembr||1995||Gnaiger E, Steinlechner-Maran R, Méndez G, Eberl T, Margreiter R (1995) Control of mitochondrial and cellular respiration by oxygen. J Bioenerg Biomembr 27:583-96.||Human|
|Gnaiger 1993 Transitions||1993||Gnaiger E (1993) Homeostatic and microxic regulation of respiration in transitions to anaerobic metabolism. In: The vertebrate gas transport cascade: Adaptations to environment and mode of life. Bicudo JEPW (ed), CRC Press, Boca Raton, Ann Arbor, London, Tokyo:358-70.||Reptiles|
|Gnaiger 1991 Soc Exp Biol Seminar Series||1991||Gnaiger E (1991) Animal energetics at very low oxygen: Information from calorimetry and respirometry. In: Strategies for gas exchange and metabolism. Woakes R, Grieshaber M, Bridges CR (eds), Soc Exp Biol Seminar Series 44, Cambridge Univ Press, London:149-71.||Annelids||Intact organism|
|Gnaiger 1983 J Exp Zool||1983||Gnaiger E (1983) Heat dissipation and energetic efficiency in animal anoxibiosis. Economy contra power. J Exp Zool 228:471-90.||Annelids|
|Skeletal muscle||Intact organism|
- Abstracts: Tissue normoxia
|Donnelly 2022 Abstract Bioblast||2022||2.1. «10+5» https://doi.org/10.26124/bec:2022-0001||Oxidative stress;RONS|
|Gnaiger 2018 AussieMit||2018||Komlodi Timea, Sobotka Ondrej, Doerrier Carolina, Gnaiger Erich (2018) Mitochondrial H2O2 production is low under tissue normoxia but high at in-vitro air-level oxygen pressure - comparison of LEAK and OXPHOS states. AussieMit 2018 Melbourne AU.||Mouse|
|Sobotka 2018 MiP2018||2018||Mouse|
|Komlodi 2017 MiP2017||2017||Mouse||Heart|
|Isolated mitochondria||Oxidative stress;RONS|
MitoPedia concepts: MiP concept