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[[File:Bioblast2022 banner.jpg|link=Bioblast_2022]]
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{{Publication
{{Publication
|title=MitoEAGLE Hypoxia Task Group (2022) The ABC of hypoxia – what is the norm? MitoFit Preprints (in prep).
|title=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.v2 — ''2022-11-14 published in [https://doi.org//10.26124/bec:2022-0012 '''Bioenerg Commun 2022.12.''']''
|authors=MitoEAGLE Hypoxia Task Group
|info=MitoFit Preprints 2022.25.v2. [[File:MitoFit Preprints pdf.png|left|160px|link=https://wiki.oroboros.at/images/4/44/Donnelly_2022_MitoFit_Hypoxia.pdf|MitoFit pdf]] [https://wiki.oroboros.at/images/4/44/Donnelly_2022_MitoFit_Hypoxia.pdf The ABC of hypoxia – what is the norm] [[File:WatchThePresentationYoutube_icon.jpg|200px|link=https://www.youtube.com/watch?v=EEo3rMa_r30&t=945s|»''Watch the Bioblast 2022 presentation''«]]
|authors=MitoFit Preprints
|year=2022
|year=2022
|journal=MitoFit Preprints
|journal=MitoFit Prep
|abstract=The terminology on ‘oxia’ ― from normoxia to hypoxia and anoxia in contrast to hyperoxia ― has a long history (Richalet 2021). Yet ambiguities persist. These are discussed in the present communication with the aim to clarify concepts, bridge the gap between different points of view, and thus facilitate future research to resolve current controversies and discrepancies. The '''ABC''' of hypoxia spans the notion of (''1'') [[hyperoxic]], [[normoxic]], and [[hypoxic]] to [[anoxic]] conditions in the atmosphere and hydrosphere to the intracellular microenvironment, (''2'') adaptation and physiological responses to oxygen availability in geological time and biological evolution (Lane 2002), and (''3'') oxygenation and hypoxia from comparative to exercise physiology in health and disease (Hochachka et al 1993). Wherever continuous oxygen gradients and discontinuous differences between compartments exist, ambient normoxia is distinguished from normoxia in biological compartments partitioned into organs, tissues, cells, and intracellular microenvironments along the respiratory cascade (Weibel 2000). Normoxia is not a norm but a reference condition for critical functions, particularly for aerobic and anaerobic energy metabolism, the control of redox state, and for oxygen sensing and hypoxic signaling in different organisms and tissues (Clanton et al 2013). Long-term evolutionary [[adaptation]] and short-term physiological, biochemical, and molecular [[acclimation]] and [[acclimatization]] re-set the functional normoxic reference points (Hochachka, Somero 2002).
|abstract=::: Version 2 ('''v2''') '''2022-07-15''' [https://wiki.oroboros.at/images/4/44/Donnelly_2022_MitoFit_Hypoxia.pdf The ABC of hypoxia – what is the norm https://doi.org/10.26124/mitofit:2022-0025.v2]
::: <small>Version 1 (v1) 2022-06-28 - [https://wiki.oroboros.at/index.php/File:Donnelly_2022_MitoFit_Hypoxia.pdf »Link to all versions«]</small>


The absolute normoxic reference point is based on a meaningful but arbitrary definition which unifies the ABC concepts of normoxia: ('''A''') '''ambient''' normoxia at sea level in the contemporary atmosphere and at air saturation of aqueous environments, ('''B''') '''biological compartmental''' O<sub>2</sub> levels at ambient normoxia of healthy organisms in the absence of environmental stress (e.g. extreme temperatures; skin diving; a stranded fish or whale), and ('''C''') '''critical functions''' maintained relative to ambient normoxia and evaluated by measurement of the response to changed oxygen conditions and oxygen kinetics (Gnaiger et al 2000). Conversely, the '''ABC''' of hypoxia and hyperoxia is concerned with deviations from these reference points caused by different mechanisms: ('''a''') '''ambient alterations''' of oxygen levels, ('''b''') '''biological O<sub>2</sub> demand''' exceeding oxygen supply under pathological or experimental limitations of convective O<sub>2</sub> transport or O<sub>2</sub> diffusion, and ('''c''') '''critical oxygen pressure''' and oxygen kinetics shifted by pathological and toxicological effects and environmental stress.
[[File:Oxia terms.png|right|250px]]
[[Donnelly 2022 Abstract Bioblast]]: Hypoxia is a condition of oxygen levels below normoxia and opposite to hyperoxia. We here define the normoxic reference state by three complementary precepts: ('''A''') ambient normoxia at sea level in the contemporary atmosphere and corresponding dissolved O<sub>2</sub> concentration at air saturation of aqueous environments; ('''B''') biological compartmental O<sub>2</sub> levels at ambient normoxia under physiological activity of healthy organisms in the absence of environmental stress (e.g. in a diving human, a stranded whale, a thermally stressed animal); and ('''C''') O<sub>2</sub> levels above the control region, i.e., where the capacity for O<sub>2</sub> consumption is not compromised by partial O<sub>2</sub> pressure as evaluated by its kinetics. Conversely, the '''abc''' of hypoxia is concerned with deviations from these reference points caused by different mechanisms: ('''a''') ambient alterations of oxygen levels; ('''b''') biological O<sub>2</sub> demand exceeding O<sub>2</sub> supply under pathological or experimental limitations of convective O<sub>2</sub> transport or O<sub>2</sub> diffusion; and ('''c''') critical oxygen pressure in oxygen kinetics shifted by pathological and toxicological effects or environmental stress. The ABC of hypoxia may be of help in the design and interpretation of ''in vitro'' and ''in vivo'' experimental studies.
<br>
|keywords=ambient, anoxia, critical O<sub>2</sub> pressure ''p''<sub>c</sub>, functional hypoxia, hyperoxia, hypoxia, limiting O<sub>2</sub> pressure ''p''<sub>l</sub>, normoxia, oxygen O<sub>2</sub>, O<sub>2</sub> concentration ''c''<sub>O<sub>2</sub></sub> [µM], O<sub>2</sub> pressure ''p''<sub>O<sub>2</sub></sub> [kPa]
|editor=Gnaiger E
|editor=Gnaiger E
|mipnetlab=AT Innsbruck Oroboros, HU Budapest Tretter L, CH Lausanne Place N
}}
}}
__TOC__
__TOC__
= The ABC of hypoxia - special BEC issue =
== Authors ==
 
:::: Questions raised by [[Val Adalberto L |Dal]] on the strategy for the '''ABC of hypoxia''' triggered the concept of a special issue of [[BEC]] on the ABC of hypoxia. The special issue is introduced by the ‘definitions paper’ on '''ABC of hypoxia - what is the norm?''' Contributors of articles to the special issue will present their (peer-reviewed) manuscripts and may contribute to the introductory definitions paper.
 
 
= Living Communication =
Last update 2022-01-10
 
== Open list of contributors ==
 
:::* [[Burtscher Martin]]<sup>1</sup>, [[Cardoso Luiza]]<sup>2</sup>, [[Cecatto Cristiane]]<sup>2</sup>, [[Donnelly Chris]]<sup>2,3</sup>, [[Gnaiger Erich]]<sup>2*</sup>, [[Kayser Bengt]]<sup>3*</sup>, [[Komlodi Timea]]<sup>2</sup>, [[Place Nicolas]]<sup>3</sup>, [[Schmitt Sabine]]<sup>2</sup>
 
::::::<sup>1</sup> Institute of Sport Science, Leopold Franzens Univ. Innsbruck, Austria
::::::<sup>2</sup> Oroboros Instruments, Innsbruck, Austria
::::::<sup>3</sup> Institute of Sport Sciences, Univ. Lausanne, Switzerland
 
::::::<sup>*</sup> Coordination: erich.gnaiger@oroboros.at, bengt.kayser@unil.ch
 
::: '''Further contacts''' (in progress)
::::* [[Chicco Adam J]], [[Chinopoulos Christos]], [[Calbet Jose AL]], [[Lane Nick]], [[Oliveira Marcus F]], [[Shick J Malcolm]], [[Val Adalberto L]], [[Zischka Hans]]
 
:::: We invite additional contributors to ensure a broad perspective of hypoxia and hyperoxia, from comparative physiology, high altitude medicine, to clinical interventions and studies of isolated mitochondria, cultured cells, to living organisms in health and disease. We should clarify step-by-step who intends to join as a contributing 'author' or as a ‘signatory’. A good example is the following reference:
::::* Amrhein V, Greenland S, McShane B (2019) Scientists rise up against statistical significance. Nature 567:305-7. -  https://www.nature.com/articles/d41586-019-00857-9 - '''with more than 800 signatories'''
 
:::: Perhaps a bad example is:
::::* [[BEC_2020.1_doi10.26124bec2020-0001.v1]] with '''666 coauthors'''. Many coauthors (''1'') ignore the message in their current publications, or (''2'') do not cite the paper if they use the message. The history of this paper has contributed to initiating the ''MitoFit Preprints'' server, but only exceptional coauthors have submitted a manuscript to ''MitoFit Preprints'' since 2019 ([[Gnaiger 2019 MitoFit_Preprints]]).
 
== Introduction ==
 
:::: For explaining normoxia and deviations from normoxia, we distinguish ('''A''') ambient oxygen conditions in the environment and ('''B''') biological compartments, from ('''C''') critical functions and signaling affected by oxygen availability below a critical oxygen pressure ('''Figure 1'''). This leads to three different but connected definitions of normoxia, which provide a reference for deriving three corresponding causes for deviations from normoxic conditions and normoxic function. The '''ABC''' of hypoxia links the three letters to the meaning of three complementary perspectives on normoxia across scientific disciplines. Several articles under the umbrella of ''ABC of oxygen'' (Bateman 1998; Leach 1998; Peacock 1998; Williams 1998; Wilmshurst 1998) use the ABC symbolically and provide overviews on specific areas related to normoxia, hypoxia, and hyperoxia.
 
[[File:TheHypeOfOxia 001.jpg|left|500px|thumb|'''Figure 1'''. '''The ABC of hypoxia''': Ambient oxygen pressure ''p''<sub>O<sub>2</sub></sub> and ''p''<sub>O<sub>2</sub></sub> in biological compartments exert different limitations on critical physiological functions. At any ambient ''p''<sub>O<sub>2</sub></sub>, intracellular partial oxygen pressure ''p''<sub>iO<sub>2</sub> varies widely between tissues and as a function of the level of physiological activities (not shown). Graphics by Paolo Cocco.]]
 
:::: Conditions called 'hypoxic' from one perspective ('''A''' ambient) are classified from another perspective as 'hyperoxic' ('''B''' biological compartments) or normoxic ('''C''' critical functions). For instance, slightly hypoxic culture conditions ('''A''') of stem cells may actually be hyperoxic compared to tissue conditions in vivo ('''B'''), but are normoxic ('''C''') if the ''p''<sub>O<sub>2</sub></sub> is above the ''p''<sub>c</sub> of mitochondrial respiration. If we consider as normoxic any intracellular ''p''<sub>O<sub>2</sub></sub> ('''B''') that is obtained at any physiological activity level of a healthy organism at ambient normoxia ('''A'''), then this definition of normoxia contrasts with the notion of physiologically induced tissue hypoxia, if the low intracellular ''p''<sub>O<sub>2</sub></sub> drops below the ''p''<sub>c</sub> of mitochondrial respiration ('''C''').


:::: The concept of harmonization instead of standardization of terminology persues a strategy that may be commonly acceptable across apparently incompatible points of view: Instead of proposing a guideline on terminology, the '''ABC''' of hypoxia and corresponding norms is intended to provide recommendations to clarify (''1'') the point of view ('''A''' versus '''B''' versus '''C''') and (''2'') the causes and processes of altered oxygen availability and supply ('''a''' versus '''b''' versus '''c'''). Then every author may consider if the important field of oxygen-regulated biological function will gain (''3'') from a consensus on general definitions potentially provided by the '''ABC''' of hypoxia.
:::* [[Donnelly Chris]]<sup>1,2</sup>, [[Schmitt Sabine]]<sup>1</sup>, [[Cecatto Cristiane]]<sup>1</sup>, [[Cardoso Luiza HD]]<sup>1</sup>, [[Komlodi Timea]]<sup>1,3</sup>, [[Place Nicolas]]<sup>2</sup>, [[Kayser Bengt]]<sup>2</sup>, [[Gnaiger Erich]]<sup>1*</sup>


== Systematic definitions of normoxia as a reference for hypoxia ==
::::::<sup>1</sup> Oroboros Instruments, Innsbruck, Austria
::::::<sup>2</sup> Institute of Sport Sciences, Univ. Lausanne, Switzerland
::::::<sup>3</sup> Department of Medical Biochemistry, Semmelweis University, Budapest, HU


=== Categories of normoxia ===
::::::<sup>*</sup> Corresponding author: erich.gnaiger@oroboros.at


:::: <big>'''A. Ambient or environmental normoxia'''</big>
::: '''Acknowledgements'''
:::: We thank [[Burtscher Martin |Martin Burtscher]] for making us aware of the ABC of oxygen, [[Chicco Adam J |Adam Chicco]] for critical comments on absolute versus evolutionary definitions of normoxia, and Malcolm J Shick and [[Val Adalberto L |Adalberto L Val]] for discussions. Chris Donnelly was supported by the Swiss National Science Foundation under grant agreement nº 194964.


:::: Comparable to referring to sea level for expressions of altitude, normoxia may be defined arbitrarily as ''p''<sub>O<sub>2</sub></sub> of c. 20 kPa (150 mmHg) at sea level in present air or in the air-saturated aqueous environment of an organism. We take the SI definition of standard pressure of 100 kPa as the reference barometric pressure and water vapour saturated air as the reference for the normoxic ''p''<sub>O<sub>2</sub></sub>.
== Correction of errors ==
::::* Figure 1: Instead of "1 kPa = 0.133322 mmHg", the correct conversion is: "1 mmHg = 0.133322 kPa".
::::* Section 2.5: Instead of "At ambient normoxia, the concentration of O<sub>2</sub> in dry air at 25 °C equals ''Φ''<sub>O<sub>2</sub></sub>·(''RT'')-1 = 0.20946·(100-3.17) kPa·(2.479 kJ·mol<sup>-1</sup>)<sup>-1</sup> = 8.18 mM", these values refer to humid (water-vapour saturated) air, and the correct relation is: ''Φ''<sub>O<sub>2</sub></sub>·(''p''<sub>b</sub>-''p''<sub>H<sub>2</sub>O</sub>*)·(''RT'')<sup>-1</sup> = 0.20946·(100-3.17) kPa·(2.479 kJ·mol<sup>-1</sup>)<sup>-1</sup> = 8.18 mM.


:::: <big>'''B. Biological compartments of the respiratory cascade – compartmental normoxia'''</big>


:::: We propose to define biological compartmental normoxia as the ''p''<sub>O<sub>2</sub></sub> in any compartment of a living organism (alveolar, arterial, venous, mixed-venous, intracellular) obtained under ambient normoxia (i.e. sea level equivalent). At environmental normoxia, compartmental ''p''<sub>O<sub>2</sub></sub> is a function of aerobic metabolic activity and O<sub>2</sub> transport from the environment to the various compartments of an organism (Weibel 2000; Keeley, Mann 2019; Ortiz-Prado et al 2019). Compartmental ''p''<sub>O<sub>2</sub></sub> may be far lower compared to ambient oxygen levels ('''A''') but may be normoxic in terms of specific critical functions (defined in '''C''').
== On definitions ==
 
:::: In isolated living cells and mitochondrial preparations – including isolated mitochondria, tissue homogenates, and permeabilized cells and tissues – ambient normoxia at air saturation of the incubation media ('''A''') must be distinguished from biologically relevant normoxia as defined by the oxygen pressure prevailing in the cellular and mitochondrial microenvironment in the tissue of the intact organism ('''B''').
 
:::: Biological compartmental normoxia ranges from ('''B<sub>r</sub>''') aerobic resting or routine steady-state activity up to ('''B<sub>max</sub>''') at maximum aerobic activity ''V''<sub>O<sub>2</sub>max</sub> sustained for only a few minutes. Routine respiration (Chabot et al 2016) is higher than standard or basal respiration due to the oxygen consumption required to sustain various routine activities, not restricted to locomotory activity but including the effects of food intake and perception. In isolated living cells studied in culture, [[ROUTINE respiration]] varies as a function of cell cycle and substrate utilization. ROUTINE respiration of living cells is under physiological control of energy turnover in the range from [[LEAK respiration]] to [[OXPHOS capacity]] (Gnaiger et al 2020). “Different media and external substrate supply modify the potential limitation of [[ET capacity]] by intracellular substrates and influence the level of ROUTINE respiration” (Gnaiger 2020).
 
:::: <big>'''C. Critical function – normoxia evaluated by function, functional normoxia'''</big>
 
:::: For any critical function, normoxic performance is defined as the biological response that does not deviate from the physiological function measured under environmental or compartmental normoxia. Whereas normoxic respiration of isolated mitochondria can be measured as a constant rate in a wide range of O<sub>2</sub> concentrations (oxyregulators; Gnaiger 2003), H<sub>2</sub>O<sub>2</sub> production is a continuous function of O<sub>2</sub> concentration (oxyconformance; Komlódi et al 2021). H<sub>2</sub>O<sub>2</sub> production, therefore, cannot be used as a critical function for defining functional normoxia.
 
:::: ‘The high affinity of cytochrome ''c'' oxidase for oxygen implies independence of mitochondrial respiration of oxygen over a wide range of oxygen levels, which gives rise to the paradigm of “oxygen regulation”, although “kinetic oxygen saturation” describes more accurately the underlying mechanism’ (Gnaiger 2003). Normoxic respiration can thus be defined as respiration at kinetic oxygen saturation, and hypoxic respiration as respiration below a critical oxygen pressure ''p''<sub>c</sub>, when the ''p''<sub>O<sub>2</sub></sub> becomes limiting and respiration shows oxyconformance. “Intracellular hypoxia is defined as ('''B''') local oxygen pressure below normoxic reference states, or ('''C''') limitation of mitochondrial respiration by oxygen levels below kinetic saturation, resulting in oxyconformance” (Gnaiger 2003).
 
=== Causes of deviations from normoxia ===
 
:::: Based on definitions of the categories ('''A''') environmental normoxia, ('''B''') compartmental normoxia, and ('''C''') functional normoxia, the causes for deviations from normoxia are separated into three categories:
 
:::: <big>'''a. Environmental hypoxia and hyperoxia'''</big>
 
::::* Hypobaric conditions: high altitude or low-pressure chamber with air
::::* Hyperbaric conditions: high-pressure chamber, diving with air
::::* Normobaric conditions: O<sub>2</sub> deprivation in the environment (environmental normobaric hypoxia), O<sub>2</sub> supplementation (environmental normobaric hyperoxia).
 
:::: <big>'''b. Compartmental hypoxia and hyperoxia'''</big>
 
::::* Environmentally induced hypoxia or hyperoxia on the compartmental level (living organism)
::::* Pathologically and toxicologicalla induced hypoxia or hyperoxia on the compartmental level (living organism)
::::* Experimental conditions for isolated organs, tissues, cells, and organelles: deviations of incubation ''p''<sub>O<sub>2</sub></sub> of experimental preparations from ('''B''') compartmental normoxia in the intact organism
 
:::: <big>'''c. Functionally induced hypoxia and hyperoxia'''</big>
 
::::* Environmental: respiratory O<sub>2</sub> depletion or photosynthetic O<sub>2</sub> accumulation in eutrophic semi-closed aqueous environments (Gnaiger 1983).
::::* Physiologically induced on the compartmental level. Hypoxia: tissue-work related; living organism at high workload of a tissue; (mal)adaptive responses of the respiratory cascade to (de)training and lifestyle. Hyperoxia: endosymbiotic algae at high light intensities (e.g. corals).
::::* Pathological-pharmacological-toxicological O<sub>2</sub>-transport related hypoxia (ischemia and stroke, anaemia, chronic heart disease, chronic obstructive pulmonary disease, disordered regional distribution of blood flow, severe COVID-19, obstructive sleep apnea, CO poisoning), inhibition or acceleration of O<sub>2</sub>-linked pathways (cyanide, rotenone, NO, ..; doping, ..).
::::* Genetic: inhibition or acceleration of O<sub>2</sub>-linked pathways (mutations, inherited diseases, knockout, knock-in).
 
:::: Maximum activity may induce compartmental hypoxia, gauged from a comparison of intracellular ''p''<sub>O<sub>2</sub></sub> ― which declines in skeletal muscle at ''V''<sub>O<sub>2</sub>max</sub> relative to routine activity (Richardson et al 2006) ― and oxygen kinetics of isolated mitochondria (Gnaiger 2001; Harris et al 2015). Since OXPHOS capacity of isolated mitochondria (Gnaiger et al 2020) is already slightly limited at intracellular tissue ''p''<sub>O<sub>2</sub></sub> observed at ''V''<sub>O<sub>2</sub>max</sub>, a high workload can entail physiological hypoxia. ''V''<sub>O<sub>2</sub>max</sub> cannot be maintained over prolonged periods of time, such that upon functionally induced hypoxia the organism returns to a normoxic steady state.
 
:::: Categories '''A''' and '''a''' appear similar, distinguished only as ('''A''') a description of a state in terms of a given ''p''<sub>O<sub>2</sub></sub>, in contrast to ('''a''') including the causes for deviations of the ''p''<sub>O<sub>2</sub></sub> from normoxia. Therefore, '''A''' and '''a''' are tightly linked.
 
== Far from normoxia ==
 
[[File:O2 log scale.png|left|500px|link=Gnaiger 2003 Adv Exp Med Biol|thumb|'''Figure 2'''. '''Deviations from ambient normoxia''': logarithmic scale of partial pressure of oxygen ''p''<sub>O<sub>2</sub></sub> (1 kPa = 0.133322 mmHg). The corresponding oxygen concentrations ''c''<sub>O<sub>2</sub></sub> [µM] is given for pure water at 25 °C. The volume fractions of air ''Φ''<sub>air</sub> [% air] and volume fractions of O<sub>2</sub> ''Φ''<sub>O<sub>2</sub></sub> [% O<sub>2</sub>] are for the standard barometric pressure of 100 kPa and corrected for a 3.2 kPa water vapor saturation pressure at 25 °C. Left: some critical and limiting ''p''<sub>O<sub>2</sub></sub>, ''p''<sub>c</sub> and ''p''<sub>l</sub>, for mammalian tissues and mitochondria. Right: limit of detection of selected methods (O2k: Oroboros Oxygraph-2k). Modified after Gnaiger (1991).]]
 
=== Extents of hypoxia: approaching anoxia ===
 
:::: There is a continuous transition of hypoxia to anoxia, which is best represented on a logarithmic scale of ''p''<sub>O<sub>2</sub></sub> ('''Figure 2'''). Respiration declines below the critical ''p''<sub>O<sub>2</sub></sub>, ''p''<sub>c</sub>, and anaerobic metabolism is stimulated below the limiting ''p''<sub>O<sub>2</sub></sub>, ''p''<sub>l</sub> (Gnaiger 1991). Only if the transition to anoxia is of interest, then further differentiation of microxia and anoxia is of technical and physiological interest taking into account the limit of detection of methods applied for determining ''p''<sub>O<sub>2</sub></sub> and different methods to detect functional responses to the presence (microxia) or absence (anoxia) of trace amounts of oxygen (Gnaiger 1993; Harrison et al 2015). Oxic versus anoxic conditions (in the presence or absence of molecular oxygen) must be distinguished from aerobic and anaerobic metabolism. Aerobic metabolism requires oxic conditions, whereas anaerobic metabolism may proceed under oxic conditions (aerobic glycolysis) or under anoxia.
 
=== Extents of hyperoxia: Experimental conditions for studies of cultured cells and isolated mitochondrial ===
 
::::* Difference between environmental and intracellular tissue normoxia (compartmental)
::::* Extend the focus on the respiratory response to effective ‘tissue hyperoxia and hypoxia’ in studies of isolated mitochondria and cells, to oxygen sensing, redox states, molecular signaling, oxidative stress, P»/O<sub>2</sub> ratios (Gnaiger et al 2000), ...
 
=== Partial pressure and concentration of oxygen ===
 
:::: Discontinuous differences of oxygen pressure, Δ''p''<sub>O<sub>2</sub></sub>, are caused by diffusion limitation across compartmental barriers, and discontinuous oxygen concentration differences, Δ''c''<sub>O<sub>2</sub></sub>, are additionally a function of oxygen solubilities in different compartments, such as the gaseous-aqueous compartments in the lung and the aqueous-membraneous compartments in the cell.
 
:::: In O<sub>2</sub> transport by convection, the total O<sub>2</sub> concentration matters in the medium that is moved from the source to the sink. O<sub>2</sub> is transported with the medium. O<sub>2</sub> carriers such as hemoglobin enhance the convectional efficacy by effectively increasing the total amount of O<sub>2</sub> transported by a volume of blood. Just having a carrier is not sufficient, but the loading of the carrier with O<sub>2</sub> at the source and unloading at the sink are essential. A larger amount of molecular O<sub>2</sub> is transported per volume of gas compared to a volume of aqueous solution. In O<sub>2</sub> diffusion by molecular dispersion of O<sub>2</sub> in a gradient of O<sub>2</sub> pressure, d''p''<sub>O<sub>2</sub></sub>/d''z'' is the driver, where Fick's law of diffusion represents a special case of the linear flux-pressure relationships which can be extended to discontinuous descriptions based on pressure differences Δ''p''<sub>O<sub>2</sub></sub> (Gnaiger 2020). In diffusion, O<sub>2</sub> is transferred across the medium, which may be facilitated by O<sub>2</sub> carriers such as myoglobin, again dependent on the loading/unloading kinetics. The O<sub>2</sub> solubility is a decisive component of O<sub>2</sub> transfer by diffusion (Hitchman, Gnaiger 1983), implicit in the diffusion coefficient or mobility (Gnaiger 2020).
 
:::: At ambient normoxia, the concentration of oxygen in dry air at 25 °C equals ''Φ''<sub>O<sub>2</sub></sub>·(''RT'')<sup>-1</sup> = 0.20946·(100-3.17) kPa·(2.479 kJ·mol<sup>-1</sup>)<sup>-1</sup> = 8.18 mM. In contrast, the oxygen concentration in air-saturated pure water is 0.255 mM or 254.7 µM. Under these conditions, the oxygen partial pressure is identical at 20.28 kPa in air and air-saturated water, but the oxygen concentration in air is 32-fold higher than in water (https://wiki.oroboros.at/index.php/Oxygen_solubility). The concept of compartmental normoxia ― and consideration of terrestrial and aqueous organisms ― raises the issue of the preference of expressing O2 ‘levels’ in terms of amount concentration ''c''<sub>O<sub>2</sub></sub> in units [mol∙L<sup>-1</sup> = M] or gas pressure ''p''<sub>O<sub>2</sub></sub> in SI units [J∙m<sup>-3</sup> = Pa]. At room temperature or 37 °C, the concentration of oxygen is 30- to 40-fold higher in the gas phase compared to the aqueous phase in equilibrium with the gas phase. Compared to the oxygen solubility ''S''<sub>O<sub>2</sub></sub> [µM∙kPa<sup>-1</sup>] in water, ''S''<sub>O<sub>2</sub></sub> in serum is 0.89 at 37 °C (Baumgärtl, Lübbers 1983) and in mitochondrial respiration medium MiR05 this solubility factor of the medium (''F''<sub>M</sub>, solubility in salt solution divided by solubility in pure water) is 0.92. Taken togerther, these are the physicochemical reasons why tracheal oxygen supply through the gas phase is very effective in supporting high oxygen demand of flying insects, and why we need red blood cells with hemoglobin to boost the total amount of oxygen carried per volume of blood.
 
:::: The ideal gas law plays a central role in elucidating the behavior of gases dissolved in aqueous solution, where O<sub>2</sub> interacts with a very different environment compared to the gas phase.
 
<big>'''Eq. 1''':  ''c''<sub>G</sub>(g) = ''p''<sub>G</sub>·(''RT'')<sup>-1</sup> </big>
 
:::: The gas law (Eq. 1) is called 'ideal', since the activity coefficient ''γ''<sub>G</sub>(g) of an ideal gas G is defined as zero. Actually, the molar volume ''V''<sub>m,G</sub>(g) = 1/''c''<sub>G</sub> of the ideal gas is 22.414 L/mol at 0 °C, whereas the real molar volume of O<sub>2</sub> is ''V''<sub>m,O<sub>2</sub></sub>(g) = 22.392 L/mol at 0 °C. The ratio ''V''<sub>m,G</sub>(g)/''V''<sub>m,O<sub>2</sub></sub>(g) is ''γ''<sub>O<sub>2</sub></sub>(g) = 22.414/22.392 = 1.001. Therefore, O<sub>2</sub>(g) behaves closely as an ideal gas at practically encountered barometric pressures. In aqueous solution, O<sub>2</sub>(aq) has a much higher activity coefficient ''γ''<sub>O<sub>2</sub></sub>(g). Defining solubility as concentration per pressure, rearranging Eq. 1, and inserting the activity coefficient ''γ''<sub>O<sub>2</sub></sub>(aq) yields,
 
<big>'''Eq. 2a''':  ''S''<sub>G</sub>(g) = ''c''<sub>G</sub>(g)·''p''<sub>G</sub><sup>-1</sup> = (''RT'')<sup>-1</sup></big>
<br>
 
<big>'''Eq. 2b''':  ''γ''<sub>O<sub>2</sub></sub>(aq)·''S''<sub>O<sub>2</sub></sub>(aq) = ''γ''<sub>O<sub>2</sub></sub>(aq)·''c''<sub>O<sub>2</sub></sub>(aq)·''p''<sub>O<sub>2</sub></sub><sup>-1</sup> = (''RT'')<sup>-1</sup> </big>
 
::::  The partial pressures of a gas in the gas phase and aqueous phase are equal at equilibium between the two phases. Pressure is general at practically encountered pressures (fugacity is the more general concept applicable in the deep sea), such that the partial pressure of an ideal gas ''p''<sub>G</sub> can be set equal to the partial pressure of a real gas ''p''<sub>O<sub>2</sub></sub>. Therefore, ''γ''<sub>O<sub>2</sub></sub>(aq) is derived as
 
<big>'''Eq. 3''':  ''γ''<sub>O<sub>2</sub></sub>(aq) = ''c''<sub>G</sub>(g)/''c''<sub>O<sub>2</sub></sub>(aq) = ''S''<sub>G</sub>(g)/''S''<sub>O<sub>2</sub></sub>(aq) </big>
[[File:O2 solubility-gaslaw.jpg|left|500px|thumb|'''Table 1'''. '''Temperature dependence of oxygen levels in the gas and aqueous phases at ambient normoxia''': ''S''<sub>G</sub>(g) and ''S''<sub>O<sub>2</sub></sub>(aq) are the gas solubilities in the gas and aqueous phase. ''γ''<sub>O<sub>2</sub></sub>(aq) is the activity coeffient of O<sub>2</sub>(aq). ''p''<sub>O<sub>2</sub></sub>* and ''c''<sub>O<sub>2</sub></sub>(aq)* are the partial pressure and concentration of O<sub>2</sub>(aq) at ambient normoxia of 100 kPa barometric pressure, at water vapour saturation and equilibrium* with the gas phase.]]
 
:::: These concepts are summarized in '''Table 1'''. In aqueous extracellular and intracellular environments, climate change is intrinsically linked to concepts of normoxic O<sub>2</sub> concentration ''c''<sub>O<sub>2</sub></sub> [µM] versus O<sub>2</sub> partial pressure ''p''<sub>O<sub>2</sub></sub> [kPa] due to the decline of O<sub>2</sub> solubility [µM/kPa] with increasing temperature.
 
 
== Notes ==
 
=== Quotes on hypoxia and normoxia ===
 
:::: Several definitions of normoxia or hypoxia are restricted to a single category or specific combination of categories and lack, therefore, generality.
 
::::* '''ABC''': ''Compared with ambient oxygen pressure 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 ''p''<sub>O<sub>2</sub></sub> in solid organs such as heart, brain, kidney, and liver (19). Considering the respiratory cascade and oxygen in the microenvironment of tissue (23, 26), it appears surprising that protein synthesis becomes inhibited in hepatocytes incubated at a “hypoxic” ''p''<sub>O<sub>2</sub></sub> of 11 kPa (80 mmHg) compared with 95 % oxygen (41), hepatocyte respiration is reduced at 9 kPa (70 mmHg (54)), and cytochrome ''c'' oxidase is reversibly inhibited at 50 μM (4 kPa or 30 mmHg (16)). Does this suggest substantial oxygen limitation of aerobic ATP production and protein synthesis to prevail under normoxia in vivo, or are responses to oxygen altered in vitro?'' ([[Gnaiger 2003 Adv Exp Med Biol]]).
 
::::* '''B''' and '''C''': ''Intracellular hypoxia is defined as local oxygen pressure below normoxic reference states, or limitation of mitochondrial respiration by oxygen levels below kinetic saturation, resulting in oxyconformance'' ([[Gnaiger 2003 Adv Exp Med Biol]]). - These are definitions for ('''B''') or ('''C''').
 
::::* '''B''' and '''C''': ''The high affinity of cytochrome ''c'' oxidase for oxygen implies independence of mitochondrial respiration of oxygen over a wide range of oxygen levels, which gives rise to the paradigm of “oxygen regulation”, although “kinetic oxygen saturation” describes more accurately the underlying mechanism''  ([[Gnaiger 2003 Adv Exp Med Biol]]). - Normoxic respiration can thus be defined as respiration at kinetic oxygen saturation, and hypoxic respiration as respiration below a critical oxygen pressure ''p''<sub>c</sub>, when the ''p''<sub>O<sub>2</sub></sub> becomes limiting and respiration shows oxyconformance.
 
::::* '''C''': Richalet (2021) refers to Opitz (1941): ‘In 1941, Opitz says, in the introduction of his review paper “Über akute Hypoxie” (About acute hypoxia): “Die Bezeichnung ‘Hypoxie’ soll immer dann verwendet werden, wenn die Sauerstoffversorgung der Gewebe gegenüber der Norm erschwert ist.” (The term “hypoxia” should always be used when the oxygen supply to the tissues is more difficult than the norm.) (40).’
 
::::* '''A''' and '''B''' versus '''C''': ''Thus mitochondrial respiration proceeds at 90 % of its hyperbolic maximum at the ''p''<sub>50</sub> of myoglobin, suggesting the possibility of a small but significant oxygen limitation even under normoxia in active muscle'' ([[Gnaiger 2003 Adv Exp Med Biol]]). - According to Opitz (1941), even oxygen-limited ''V''<sub>O<sub>2</sub>max</sub> under normoxia ('''A''') would be considered a physiological norm for the healthy trained person, and hence functionally normoxic - in terms of normal oxygen delivery to the active muscle tissue ('''B'''). From the perspective of mitochondrial respiration at such a physiologically induced intracellular low ''p''<sub>O<sub>2</sub></sub>, this is a hypoxic condition relative to the critical ''p''<sub>O<sub>2</sub></sub> (''p''<sub>c</sub>) and kinetic oxygen saturation ('''C'''). In this context it is important to consider the following four points:
::::::* (''1'') At OXPHOS capacity the ''p''<sub>50</sub> and hence ''p''<sub>c</sub> is higher than under conditions of ADP-limited lower respiratory activity with a minimum at LEAK respiration. Mitochondrial respiration becomes more ‘sensitive’ to ''p''<sub>O<sub>2</sub></sub> at high levels of activation (Gnaiger et al 1998; Gnaiger 2001). Therefore, low intracellular tissue ''p''<sub>O<sub>2</sub></sub> at ''V''<sub>O<sub>2</sub>max</sub> would be considered functionally normoxic for LEAK respiration but functionally hypoxic for OXPHOS capacity. At ''V''<sub>O<sub>2</sub>max</sub>, muscle mitochondria operate slightly below OXPHOS capacity if respiration is oxygen limited, and at OXPHOS capacity in untrained persons who are not oxygen limited but mitochondrial-capacity limited (Richardson et al 1999; Gifford et al 2016). This relates to apparent mitochondrial excess capacities in muscle (Gnaiger et al 1998).
::::::* (''2'') ''even under normoxia'' – this refers to ambient normoxia ('''A'''), perhaps not made sufficiently clear – therefore, we need the '''ABC'''.
::::::* (''3'') ''in active muscle'' (from the point of view of aerobic activity the maximum is at ''V''<sub>O<sub>2</sub>max</sub>): intracellular ''p''<sub>O<sub>2</sub></sub> is lower than at rest or routine activity. Therefore, muscle ‘runs’ into the paradox that ''p''<sub>O<sub>2</sub></sub> is lower while mitochondria become more limited at low ''p''<sub>O<sub>2</sub></sub> in the OXPHOS state compared to the LEAK state. This explains the adaption to aerobic training under (sea-level) normoxia with increased mt-biogenesis, in contrast to high-altitude adaption with lower mt-density.
::::::* (''4'') ‘Intracellular tissue normoxia’ must be used with further specification in terms of either ('''B''') if short-term maximum activity is included without restriction to steady-state routine states, or ('''C''') defining tissue-work induced hypoxia in terms of critical functions limited by ''p''<sub>O<sub>2</sub></sub>.
 
::::* '''A''' versus '''B''': ''.. stem cells are conventionally incubated under non-physiological air O<sub>2</sub> tension (21 %). Therefore, the study of mechanisms and signaling activated at lower O<sub>2</sub> tension, such as those existing under native microenvironments (referred to as hypoxia), represent an effective strategy to define if O<sub>2</sub> is essential in preserving naïve stemness potential as well as in modulating their differentiation'' ([[Di 2021 Cells]]).
 
::::* Unclear: ('''B''' and '''C'''). Tissue hypoxia is defined as a condition in which the cells of a tissue have abnormal oxygen utilization such that the tissue is experiencing anaerobic metabolism (4) [[Third European Consensus Conference in Intensive Care Medicine 1996 Am J Respir Crit Care Med]].
 
::::* '''A''' or '''B.c''': Hypoxia - ‘a condition in which there is not enough oxygen available to the blood and body tissues’ (https://dictionary.cambridge.org/fr/dictionnaire/anglais/hypoxia, retrieved 2021-12-18).
 
::::* '''A''' or '''B.c''': Hypoxia – ‘deficiency in the amount of oxygen delivered to the body tissues’ (https://www.collinsdictionary.com/dictionary/english/hypoxia, retrieved 2021-12-19)
 
::::* '''A''' or '''B.c''': Hypoxia – ‘a deficiency of oxygen reaching the tissues of the body’ (https://www.merriam-webster.com/dictionary/hypoxia, retrieved 2021-12-19)
 
::::* '''C.c''': Hypoxia is defined as functional hypoxia by the European Environmental Agency as “a state of low oxygen concentration in water and sediments, relative to the needs of most aerobic species” (https://www.eea.europa.eu/help/glossary/chm-biodiversity/hypoxia; retrieved 2021-12-14).
 
=== Various 'oxia' terms ===
 
[[File:Oxia terms.png|right|250px]]
:::: For harmonization, the following ‘oxia’ terms are linked to the '''ABC''' categories.
 
::::* '''B''': “Physoxia: physiological oxygen level in peripheral tissues with an average of approximately 6 % (ranging from approximately 7.5 % to 4 % depending on the tissue; lower limit approximately 1 %). For experimental studies, 5 % is the proposed compromise since this is often used” (McKeown 2014). ― The term ‘physoxia’ or ‘physioxia’ (Carreau et al 2011) suggests physiological control in contrast to abiotic environmental control. Without further specification, physoxia may be interpreted as ('''B.a''') compartmental oxygen level under any environmental conditions, ('''B.c''') for any level of physiological activity, and ('''Ba.c''') their combination (e.g. muscle ''p''<sub>O<sub>2</sub></sub> at ''V''<sub>O<sub>2</sub>max</sub> at high altitude). In addition, physoxia does not separate the categories '''B''' and '''C''' of normoxia, and it may include any pathological cause of deviation from normoxia.
 
::::* '''C.b''': “Pathological hypoxia: shows persistence of poor oxygenation suggesting disruption to normal homeostasis. Below this level pathological hypoxia applies” (McKeown 2014). Besides regulation of hypoxia response genes, the critical physiological function should be specified. ― High altitude exposure may result in prolonged poor oxygenation of tissues. But is this pathological hypoxia?
 
 
=== On definitions ===


::::* ''Definitions always leak at the margins, where experts delight in posing counterexamples for their peers to ponder. Fortunately, the typical cases are clear enough that a little fuzziness around the edges does not interfere with the larger picture'' ([[Miller 1991 Scientific American Library]]).
::::* ''Definitions always leak at the margins, where experts delight in posing counterexamples for their peers to ponder. Fortunately, the typical cases are clear enough that a little fuzziness around the edges does not interfere with the larger picture'' ([[Miller 1991 Scientific American Library]]).
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== References and weblinks ==
== References ==
 
{{#ask:[[Additional label::MitoFit2022Hypoxia]]
{{#ask:[[Additional label::MitoFit2022Hypoxia]]
| mainlabel=Link
| mainlabel=Link
|?Has info=View
|?Has title=Reference
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:: '''MitoPedia keywords'''
{{Template:Keywords: hypoxia, normoxia, hyperoxia}}
:::: The following MitoPedia terms contribute to and will be updated according to the ABC.
::::» [[Aerobic]]
::::» [[Anaerobic]]
::::» [[Anoxia]]
::::» [[Hyperoxia]]
::::» [[Hypoxia]]
::::» [[Microxia]]
::::» [[Normoxia]]
 
:: '''Current conferences'''
 
::::» https://www.rsc.org/events/detail/3610/keystone-symposia-hypoxia-molecular-mechanisms-of-oxygen-sensing-and-response-pathways
::::» https://www.hypoxia.net/
::::» https://www.dwscientific.com/2nd-whitley-hypoxia-symposium
::::» https://waset.org/hypoxia-exercise-and-hypoxic-exposure-conference-in-january-2022-in-bali
::::» https://conferenceindex.org/event/international-conference-on-hypoxia-inducible-factors-and-oxygen-biology-ichifob-2022-may-dubai-ae


{{Labeling
{{Labeling

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Donnelly 2022 MitoFit Hypoxia

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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.v2 — 2022-11-14 published in Bioenerg Commun 2022.12.

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Version 2 (v2) 2022-07-15 The ABC of hypoxia – what is the norm https://doi.org/10.26124/mitofit:2022-0025.v2
Version 1 (v1) 2022-06-28 - »Link to all versions«
Oxia terms.png

Donnelly 2022 Abstract Bioblast: Hypoxia is a condition of oxygen levels below normoxia and opposite to hyperoxia. We here define the normoxic reference state by three complementary precepts: (A) ambient normoxia at sea level in the contemporary atmosphere and corresponding dissolved O2 concentration at air saturation of aqueous environments; (B) biological compartmental O2 levels at ambient normoxia under physiological activity of healthy organisms in the absence of environmental stress (e.g. in a diving human, a stranded whale, a thermally stressed animal); and (C) O2 levels above the control region, i.e., where the capacity for O2 consumption is not compromised by partial O2 pressure as evaluated by its kinetics. Conversely, the abc of hypoxia is concerned with deviations from these reference points caused by different mechanisms: (a) ambient alterations of oxygen levels; (b) biological O2 demand exceeding O2 supply under pathological or experimental limitations of convective O2 transport or O2 diffusion; and (c) critical oxygen pressure in oxygen kinetics shifted by pathological and toxicological effects or environmental stress. The ABC of hypoxia may be of help in the design and interpretation of in vitro and in vivo experimental studies.

• Keywords: ambient, anoxia, critical O2 pressure pc, functional hypoxia, hyperoxia, hypoxia, limiting O2 pressure pl, normoxia, oxygen O2, O2 concentration cO2 [µM], O2 pressure pO2 [kPa] • Bioblast editor: Gnaiger E • O2k-Network Lab: AT Innsbruck Oroboros, HU Budapest Tretter L, CH Lausanne Place N

Authors

1 Oroboros Instruments, Innsbruck, Austria
2 Institute of Sport Sciences, Univ. Lausanne, Switzerland
3 Department of Medical Biochemistry, Semmelweis University, Budapest, HU
* Corresponding author: erich.gnaiger@oroboros.at
Acknowledgements
We thank Martin Burtscher for making us aware of the ABC of oxygen, Adam Chicco for critical comments on absolute versus evolutionary definitions of normoxia, and Malcolm J Shick and Adalberto L Val for discussions. Chris Donnelly was supported by the Swiss National Science Foundation under grant agreement nº 194964.

Correction of errors

  • Figure 1: Instead of "1 kPa = 0.133322 mmHg", the correct conversion is: "1 mmHg = 0.133322 kPa".
  • Section 2.5: Instead of "At ambient normoxia, the concentration of O2 in dry air at 25 °C equals ΦO2·(RT)-1 = 0.20946·(100-3.17) kPa·(2.479 kJ·mol-1)-1 = 8.18 mM", these values refer to humid (water-vapour saturated) air, and the correct relation is: ΦO2·(pb-pH2O*)·(RT)-1 = 0.20946·(100-3.17) kPa·(2.479 kJ·mol-1)-1 = 8.18 mM.


On definitions

  • Definitions always leak at the margins, where experts delight in posing counterexamples for their peers to ponder. Fortunately, the typical cases are clear enough that a little fuzziness around the edges does not interfere with the larger picture (Miller 1991 Scientific American Library).
  • A lexicographer tries, not always successfully, to steer a course between incomprehension and miscomprehension. .. writing definitions is a difficult and little-appreciated art (Miller 1991 Scientific American Library).
  • Full standardisation of definitions and analytical procedures could be feasible for new research efforts. .. For existing datasets and studies, harmonisation attempts to achieve some, but not necessarily perfect, homogeneity of definitions might need substantial effort and coordination. .. Large consortia and collaborations can allow the use of a common language among investigators for clinical definitions, laboratory measurements, and statistical analyses (Ioannidis 2014 Lancet).


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Keywords: Oxia terms

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TermAbbreviationDescription
AerobicoxThe 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.
AnaerobicAnaerobic 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.
AnoxiaanoxIdeally 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 pressurepcThe 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.
HyperoxiahyperoxHyperoxia 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.
HypoxiahypoxHypoxia (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 oxygenpO2,iPhysiological, 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 pressureplThe 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.
MicroxiamicroxMicroxia (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.
Normoxianormox
Oxia
Normoxia is a reference state, frequently considered as air-level oxygen pressure at sea level (c. 20 kPa in water vapor saturated air) as environmental normoxia. Intracellular tissue normoxia is variable between organisms and tissues, and intracellular oxygen pressure is frequently well below air-level pO2 as a result of cellular (mainly mitochondrial) oxygen consumption and oxygen gradients along the respiratory cascade. Oxygen pressure drops from ambient normoxia of 20 kPa to alveolar normoxia of 13 kPa, while extracellular normoxia may be as low as 1 to 5 kPa in solid organs such as heart, brain, kidney and liver. Pericellular pO2 of cells growing in monolayer cell cultures may be 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.
General
» Oxygen, dioxygen, O2
» Intracellular oxygen
» Oxygen pressure
» Oxygen solubility
» Gas pressure
» pascal
» Pressure
» Barometric pressure
» Concentration
Related keyword lists
» Keywords: Oxygen signal
» Keywords: Concentration and pressure

Publications: Tissue normoxia

 YearReferenceOrganismTissue;cellPreparationsStressDiseases
Donnelly 2022 MitoFit Hypoxia2022Donnelly 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.v2 — 2022-11-14 published in Bioenerg Commun 2022.12.Oxidative stress;RONS
Hypoxia
Donnelly 2022 BEC2022Donnelly 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.v2. https://doi.org/10.26124/bec:2022-0012.v2Oxidative stress;RONS
Hypoxia
DiProspero 2021 Toxicol In Vitro2021DiProspero TJ, Dalrymple E, Lockett MR (2021) Physiologically relevant oxygen tensions differentially regulate hepatotoxic responses in HepG2 cells. https://doi.org/10.1016/j.tiv.2021.105156LiverIntact cellsHypoxia
Stepanova 2020 Methods Cell Biol2020Stepanova A, Galkin A (2020) Measurement of mitochondrial H2O2 production under varying O2 tensions. https://doi.org/10.1016/bs.mcb.2019.12.008MouseNervous systemIsolated mitochondriaOxidative stress;RONS
Ast 2019 Nat Metab2019Ast 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 Rev2019Keeley 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 Neurochem2018Stepanova 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.MouseNervous systemIsolated mitochondriaIschemia-reperfusion
Oxidative stress;RONS
Stepanova 2018 J Cereb Blood Flow Metab2018Stepanova 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.RatNervous systemIsolated mitochondriaHypoxia
Ischemia-reperfusion
Stuart 2018 Oxid Med Cell Longev2018Stuart 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 Metab2017Stepanova 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.MouseNervous systemIsolated mitochondriaIschemia-reperfusion
Harrison 2015 J Appl Physiol2015Harrison 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.00146.2015Mouse
Bovines		HeartIsolated mitochondriaHypoxia
Carreau 2011 J Cell Mol Med2011Carreau 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 Physiol2006Richardson 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.2005.102327HumanSkeletal muscleHypoxia
Pettersen 2005 Cell Prolif2005Pettersen 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 Biol2003Gnaiger E (2003) Oxygen conformance of cellular respiration. A perspective of mitochondrial physiology. https://doi.org/10.1007/978-1-4419-8997-0_4Human
Rat		Heart
Liver
Endothelial;epithelial;mesothelial cell
Fibroblast		Intact cells
Permeabilized cells
Permeabilized tissue
Isolated mitochondria
Oxidase;biochemical oxidation
Gnaiger 2001 Respir Physiol2001Gnaiger 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)00307-3Human
Rat		Heart
Liver
Endothelial;epithelial;mesothelial cell
HUVEC		Intact cells
Isolated mitochondria		Oxidative stress;RONS
Gnaiger 2000 Proc Natl Acad Sci U S A2000Gnaiger 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. https://doi.org/10.1073/pnas.97.20.11080Rat
Artemia
Crustaceans		LiverIsolated mitochondria
Gnaiger 1998 Biochim Biophys Acta1998Gnaiger 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. https://doi.org/10.1016/S0005-2728(98)00076-0RatHeart
Liver		Isolated mitochondria
Gnaiger 1998 J Exp Biol1998Gnaiger 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.201.8.1129Human
Rat		Heart
Liver
Endothelial;epithelial;mesothelial cell
HUVEC		Isolated mitochondria
Enzyme
Oxidase;biochemical oxidation
Intact cells
Gnaiger 1995 J Bioenerg Biomembr1995Gnaiger E, Steinlechner-Maran R, Méndez G, Eberl T, Margreiter R (1995) Control of mitochondrial and cellular respiration by oxygen. https://doi.org/10.1007/BF02111656Human
Rat		Liver
Endothelial;epithelial;mesothelial cell
HUVEC		Isolated mitochondria
Intact cells
Gnaiger 1993 Transitions1993Gnaiger 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
Fishes
Crustaceans
Annelids		Intact organism
Gnaiger 1991 Soc Exp Biol Seminar Series1991Gnaiger 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.AnnelidsIntact organism
Gnaiger 1983 J Exp Zool1983Gnaiger E (1983) Heat dissipation and energetic efficiency in animal anoxibiosis. Economy contra power. J Exp Zool 228:471-90.Annelids
Molluscs		Skeletal muscleIntact organism
Abstracts: Tissue normoxia
 YearReferenceOrganismTissue;cellPreparationsStressDiseases
Donnelly 2022 Abstract Bioblast20222.1. «10+5»
Donnelly Chris
Donnelly Chris, Schmitt S, Cecatto C, Cardoso L, Komlodi T, Place N, Kayser B, Gnaiger E (2022) The ABC of hypoxia – what is the norm. Bioblast 2022: BEC Inaugural Conference. In: https://doi.org/10.26124/bec:2022-0001
»MitoFit Preprint« »Watch the presentation«		Oxidative stress;RONS
Hypoxia
Gnaiger 2018 AussieMit2018Komlodi 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
Saccharomyces cerevisiae		Heart
Nervous system		Isolated mitochondria
Intact cells		Oxidative stress;RONS
Hypoxia
Sobotka 2018 MiP20182018
Ondrej Sobotka
Measurement of ROS production under hypoxia and unexpected methodological pitfalls of Amplex UltraRed assay.		Mouse
Saccharomyces cerevisiae		Heart
Nervous system		Isolated mitochondriaHypoxia
Komlodi 2017 MiP20172017
Timea Komlodi
H2O2 production under hypoxia in brain and heart mitochondria: does O2 concentration matter?		MouseHeart
Nervous system		Isolated mitochondriaOxidative stress;RONS
Hypoxia



Labels: MiParea: Respiration, Comparative MiP;environmental MiP, Exercise physiology;nutrition;life style 

Stress:Oxidative stress;RONS, Hypoxia 



Regulation: Aerobic glycolysis, Flux control, Temperature  Coupling state: ROUTINE 

HRR: Oxygraph-2k 

Tissue normoxia 

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