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Difference between revisions of "Donnelly 2022 MitoFit Hypoxia"

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== Introduction ==
== Introduction ==


[[File:TheHypeOfOxia 001.jpg|right|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.]]
:::: 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.
:::: 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''').
:::: 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''').
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== Far from normoxia ==
== Far from normoxia ==


[[File:O2 log scale.png|right|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).]]
[[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 ===
=== Extents of hypoxia: approaching anoxia ===
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:::: 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,
:::: 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,


[[File:O2 solubility-gaslaw.jpg|right|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.]]
  <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>
  <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>
  <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>


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  <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>
  <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.
:::: 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 ==
== Notes ==

Revision as of 12:04, 12 January 2022

Publications in the MiPMap
MitoEAGLE Hypoxia Task Group (2022) The ABC of hypoxia – what is the norm? MitoFit Preprints (in prep).


MitoEAGLE Hypoxia Task Group (2022) MitoFit Preprints

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).

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 O2 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 O2 demand exceeding oxygen supply under pathological or experimental limitations of convective O2 transport or O2 diffusion, and (c) critical oxygen pressure and oxygen kinetics shifted by pathological and toxicological effects and environmental stress.

Bioblast editor: Gnaiger E

The ABC of hypoxia - special BEC issue

Questions raised by 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

1 Institute of Sport Science, Leopold Franzens Univ. Innsbruck, Austria
2 Oroboros Instruments, Innsbruck, Austria
3 Institute of Sport Sciences, Univ. Lausanne, Switzerland
* Coordination: [email protected], [email protected]
Further contacts (in progress)
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:
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.
Figure 1. The ABC of hypoxia: Ambient oxygen pressure pO2 and pO2 in biological compartments exert different limitations on critical physiological functions. At any ambient pO2, intracellular partial oxygen pressure piO2 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 pO2 is above the pc of mitochondrial respiration. If we consider as normoxic any intracellular pO2 (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 pO2 drops below the pc 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.

Systematic definitions of normoxia as a reference for hypoxia

Categories of normoxia

A. Ambient or environmental normoxia
Comparable to referring to sea level for expressions of altitude, normoxia may be defined arbitrarily as pO2 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 pO2.
B. Biological compartments of the respiratory cascade – compartmental normoxia
We propose to define biological compartmental normoxia as the pO2 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 pO2 is a function of aerobic metabolic activity and O2 transport from the environment to the various compartments of an organism (Weibel 2000; Keeley, Mann 2019; Ortiz-Prado et al 2019). Compartmental pO2 may be far lower compared to ambient oxygen levels (A) but may be normoxic in terms of specific critical functions (defined in C).
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 (Br) aerobic resting or routine steady-state activity up to (Bmax) at maximum aerobic activity VO2max 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).
C. Critical function – normoxia evaluated by function, functional normoxia
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 O2 concentrations (oxyregulators; Gnaiger 2003), H2O2 production is a continuous function of O2 concentration (oxyconformance; Komlódi et al 2021). H2O2 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 pc, when the pO2 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:
a. Environmental hypoxia and hyperoxia
  • Hypobaric conditions: high altitude or low-pressure chamber with air
  • Hyperbaric conditions: high-pressure chamber, diving with air
  • Normobaric conditions: O2 deprivation in the environment (environmental normobaric hypoxia), O2 supplementation (environmental normobaric hyperoxia).
b. Compartmental hypoxia and hyperoxia
  • 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 pO2 of experimental preparations from (B) compartmental normoxia in the intact organism
c. Functionally induced hypoxia and hyperoxia
  • Environmental: respiratory O2 depletion or photosynthetic O2 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 O2-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 O2-linked pathways (cyanide, rotenone, NO, ..; doping, ..).
  • Genetic: inhibition or acceleration of O2-linked pathways (mutations, inherited diseases, knockout, knock-in).
Maximum activity may induce compartmental hypoxia, gauged from a comparison of intracellular pO2 ― which declines in skeletal muscle at VO2max 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 pO2 observed at VO2max, a high workload can entail physiological hypoxia. VO2max 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 pO2, in contrast to (a) including the causes for deviations of the pO2 from normoxia. Therefore, A and a are tightly linked.

Far from normoxia

Figure 2. Deviations from ambient normoxia: logarithmic scale of partial pressure of oxygen pO2 (1 kPa = 0.133322 mmHg). The corresponding oxygen concentrations cO2 [µM] is given for pure water at 25 °C. The volume fractions of air Φair [% air] and volume fractions of O2 ΦO2 [% O2] 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 pO2, pc and pl, 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 pO2 (Figure 2). Respiration declines below the critical pO2, pc, and anaerobic metabolism is stimulated below the limiting pO2, pl (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 pO2 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»/O2 ratios (Gnaiger et al 2000), ...

Partial pressure and concentration of oxygen

Discontinuous differences of oxygen pressure, ΔpO2, are caused by diffusion limitation across compartmental barriers, and discontinuous oxygen concentration differences, ΔcO2, 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 O2 transport by convection, the total O2 concentration matters in the medium that is moved from the source to the sink. O2 is transported with the medium. O2 carriers such as hemoglobin enhance the convectional efficacy by effectively increasing the total amount of O2 transported by a volume of blood. Just having a carrier is not sufficient, but the loading of the carrier with O2 at the source and unloading at the sink are essential. A larger amount of molecular O2 is transported per volume of gas compared to a volume of aqueous solution. In O2 diffusion by molecular dispersion of O2 in a gradient of O2 pressure, dpO2/dz 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 ΔpO2 (Gnaiger 2020). In diffusion, O2 is transferred across the medium, which may be facilitated by O2 carriers such as myoglobin, again dependent on the loading/unloading kinetics. The O2 solubility is a decisive component of O2 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 ΦO2·(RT)-1 = 0.20946·(100-3.17) kPa·(2.479 kJ·mol-1)-1 = 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 cO2 in units [mol∙L-1 = M] or gas pressure pO2 in SI units [J∙m-3 = 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 SO2 [µM∙kPa-1] in water, SO2 in serum is 0.89 at 37 °C (Baumgärtl, Lübbers 1983) and in mitochondrial respiration medium MiR05 this solubility factor of the medium (FM, 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 O2 interacts with a very different environment compared to the gas phase.
Eq. 1:  cG(g) = pG·(RT)-1 
The gas law (Eq. 1) is called 'ideal', since the activity coefficient γG(g) of an ideal gas G is defined as zero. Actually, the molar volume Vm,G(g) = 1/cG of the ideal gas is 22.414 L/mol at 0 °C, whereas the real molar volume of O2 is Vm,O2(g) = 22.392 L/mol at 0 °C. The ratio Vm,G(g)/Vm,O2(g) is γO2(g) = 22.414/22.392 = 1.001. Therefore, O2(g) behaves closely as an ideal gas at practically encountered barometric pressures. In aqueous solution, O2(aq) has a much higher activity coefficient γO2(g). Defining solubility as concentration per pressure, rearranging Eq. 1, and inserting the activity coefficient γO2(aq) yields,
Eq. 2a:  SG(g) = cG(g)·pG-1 = (RT)-1


Eq. 2b:  γO2(aq)·SO2(aq) = γO2(aq)·cO2(aq)·pO2-1 = (RT)-1 
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 pG can be set equal to the partial pressure of a real gas pO2. Therefore, γO2(aq) is derived as
Eq. 3:  γO2(aq) = cG(g)/cO2(aq) = SG(g)/SO2(aq) 

Table 1. Temperature dependence of oxygen levels in the gas and aqueous phases at ambient normoxia: SG(g) and SO2(aq) are the gas solubilities in the gas and aqueous phase. γO2(aq) is the activity coeffient of O2(aq). pO2* and cO2(aq)* are the partial pressure and concentration of O2(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 O2 concentration cO2 [µM] versus O2 partial pressure pO2 [kPa] due to the decline of O2 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 pO2 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” pO2 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 pc, when the pO2 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 p50 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 VO2max 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 pO2, this is a hypoxic condition relative to the critical pO2 (pc) and kinetic oxygen saturation (C). In this context it is important to consider the following four points:
  • (1) At OXPHOS capacity the p50 and hence pc is higher than under conditions of ADP-limited lower respiratory activity with a minimum at LEAK respiration. Mitochondrial respiration becomes more ‘sensitive’ to pO2 at high levels of activation (Gnaiger et al 1998; Gnaiger 2001). Therefore, low intracellular tissue pO2 at VO2max would be considered functionally normoxic for LEAK respiration but functionally hypoxic for OXPHOS capacity. At VO2max, 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 VO2max): intracellular pO2 is lower than at rest or routine activity. Therefore, muscle ‘runs’ into the paradox that pO2 is lower while mitochondria become more limited at low pO2 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 pO2.
  • A versus B: .. stem cells are conventionally incubated under non-physiological air O2 tension (21 %). Therefore, the study of mechanisms and signaling activated at lower O2 tension, such as those existing under native microenvironments (referred to as hypoxia), represent an effective strategy to define if O2 is essential in preserving naïve stemness potential as well as in modulating their differentiation (Di 2021 Cells).

Various 'oxia' terms

Oxia terms.png
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 pO2 at VO2max 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).
  • 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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MitoPedia keywords
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


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