Gnaiger 1993 Transitions
|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.|
Abstract: • Keywords: Twin-Flow
• O2k-Network Lab: AT Innsbruck Gnaiger E
- 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.
- Common linear regression procedures, and linear and static thinking in general, may conceal the diversity of physiological patterns which have evolved as adaptations to the variety and dynamics of natural environments.
- The microxic pO2 range spans from pO2>0 kPa to the rather arbitrary region of the microxic-hypoxic transition at c. 0.1 to 1 kPa (0.8 to 7.5 mmHg; 0.5 to 5 % air saturation). This upper limit of the microxic range can be explained in terms of cellular physiology, as the range of pc values in isolated cells, e.g. passive and active myocytes (31). The microxic region thus incorporates low oxygen conditions which are difficult to monitor by conventional methods (8).
- .. 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.
- Respiratory and calorimetric measurements at low oxygen require extreme care to prevent the diffusion of oxygen, and highly sensitive instruments are required to measure the oxygen and heat fluxes which decline to a fraction of the fully aerobic fluxes (6; 8; 10).
- 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.
- Contrary to the practice to read English from left to right, a respiratory oxygen flux/pressure relation is inevitably studied from right to left: The curve is not seen to increase with pO2 but to fall from normoxia to hypoxia, as it does in a closed respirometer. The decline of the flux/pressure relation toward the left is the traditional criterion for the conforming pattern. The plot may terminate at some arbitrary value without further attention as to the shape at low oxygen levels (Fig. 1; curve II).
- A fundamentally different interpretation of curve II (Fig. 1) is suggested by simply reading the graph from the intercept, the anoxic condition (alien to us humans) to normoxia (where we are from the beginning). The pattern of both the homeostatic regulator and the microxic regulator shows a steep increase of oxygen flux, JO2 [relative units or nmol O2·s-1·g-1], with pO2 (Fig. 2). This steep JO2/pO2 slope in the microxic to hypoxic region distinguishes the microxic regulator from the true conformer.
- Within the pO2 interval from zero oxygen to a partial pressure pm, microxic regulation maintains a slope steeper than in the conformer, at >5% normoxic flux per kPa O2. The slope levels off above the pm to <5 % per kPa. In the limit, the pm merges with the critical pO2, pc, in the pattern of a homeostatic regulator (Fig. 2).
- A necessary requirement for the quantitative assessment of the pm value is the measurement of oxygen flux at pO2 levels well below the apparently linear hypoxic range.
- 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 (9).
- For comparison of the oxygen dependence, the parameters derived from mathematical models (20; 27) are less informative than the set of curves themselves. Complex patterns should not any longer be confined into categories such as oxyconformity and oxyregulation, nor should we place too much weight on some typical values such as pc or pm, since these have different significance depending on the actual environmental oxygen regime. The patterns are best seen in normalized flux/pressure diagrams, and can thus be related to the relevant environmental oxygen regime.
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
|Donnelly 2022 BEC||BEC 2022.12||Donnelly C, Schmitt S, Cecatto C, Cardoso LHD, Komlódi T, Place N, Kayser B, Gnaiger E (2022) The ABC of hypoxia – what is the norm. Bioenerg Commun 2022.12. https://doi.org/10.26124/bec:2022-0012||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. https://doi.org/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. https://doi.org/10.1016/bs.mcb.2019.12.008||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. https://doi.org/10.1152/physrev.00041.2017|
|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|
|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|
|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 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. 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. https://doi.org/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. https://doi.org/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. https://doi.org/10.1007/978-1-4419-8997-0_4||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. https://doi.org/10.1073/pnas.97.20.11080||Rat|
|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. https://doi.org/10.1242/jeb.201.8.1129||Human|
|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 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. https://doi.org/10.1007/BF02111656||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 |
|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|
Labels: MiParea: Respiration, Comparative MiP;environmental MiP
Organism: Reptiles, Fishes, Crustaceans, Annelids
Preparation: Intact organism
Regulation: Aerobic glycolysis, Oxygen kinetics Coupling state: ROUTINE
CaloRespirometry, Tissue normoxia, Twin-Flow, MitoFit2022Hypoxia