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{{Publication
{{Publication
|title=Gnaiger E (2003) Oxygen conformance of cellular respiration. A perspective of mitochondrial physiology. Adv Exp Med Biol 543: 39-55.
|title=Gnaiger E (2003) Oxygen conformance of cellular respiration. A perspective of mitochondrial physiology. https://doi.org/10.1007/978-1-4419-8997-0_4
|info=[http://www.ncbi.nlm.nih.gov/pubmed/14713113 PMID: 14713113]
|info=Adv Exp Med Biol 543:39-55. [http://www.ncbi.nlm.nih.gov/pubmed/14713113 PMID: 14713113], [[File:PDF.jpg|100px|link=http://www.bioblast.at/images/e/e9/Gnaiger_2003_Adv_Exp_Med_Biol.pdf |Bioblast pdf]]
|authors=Gnaiger E
|authors=Gnaiger Erich
|year=2003
|year=2003
|journal=Adv Exp Med Biol
|journal=Adv Exp Med Biol
|abstract=Oxygen pressure declines from normoxic air-level to the microenvironment of mitochondria where cytochrome ''c'' oxidase ([[CIV]]) reduces oxygen to water at oxygen levels as low as 0.3 kPa (2 Torr; 3 μM; 1.5% air saturation). Intracellular hypoxia is defined as (1) local oxygen pressure below normoxic reference states, or (2) limitation of mitochondrial respiration by oxygen levels below kinetic saturation, resulting in oxyconformance. [[High-resolution respirometry]] provides the methodology to measure mitochondrial and cellular oxygen kinetics in the relevant low oxygen range <1 kPa (7.5 mmHg; 9-10 μM; 5% air saturation). Respiration of isolated heart mitochondria follows hyperbolic oxygen kinetics with half-saturating oxygen pressure, ''p''<sub>50</sub>, of 0.04 kPa (0.3 Torr; 0.4 μM) in ADP-stimulated [[State 3]]. 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. Any impairment of oxygen delivery, therefore, induces oxyconformance. In addition, a shift of mitochondrial oxygen kinetics to the right, particularly by competitive inhibition of CIV by NO, causes a further depression of respiration and a compensatory increase of local oxygen pressure. Above 1 kPa, mitochondrial oxygen uptake increases above hyperbolic saturation, which is probably due to oxygen radical production rather than the kinetics of CIV. In cultured cells, the pronounced oxygen uptake above mitochondrial saturation at air-level oxygen pressure cannot be inhibited by rotenone and antimycin A, amounting to >20% of [[ROUTINE respiration]] in fibroblasts. Biochemical models of oxyconformance of CIV are evaluated relative to patterns of intracellular oxygen distribution in the tissue and enzyme turnover in vivo, considering the kinetic effects of CIV excess capacity on flux through the mitochondrial electron transfer system.
|abstract=Oxygen pressure declines from normoxic air-level to the microenvironment of mitochondria where cytochrome ''c'' oxidase ([[Complex_IV|CIV]]) reduces oxygen to water at oxygen levels as low as 0.3 kPa (2 Torr; 3 μM; 1.5 % air saturation). Intracellular hypoxia is defined as (''1'') local oxygen pressure below normoxic reference states, or (''2'') limitation of mitochondrial respiration by oxygen levels below kinetic saturation, resulting in oxyconformance. [[High-resolution respirometry]] provides the methodology to measure mitochondrial and cellular oxygen kinetics in the relevant low oxygen range <1 kPa (7.5 mmHg; 9-10 μM; 5 % air saturation). Respiration of isolated heart mitochondria follows hyperbolic oxygen kinetics with half-saturating oxygen pressure, ''p''<sub>50</sub>, of 0.04 kPa (0.3 Torr; 0.4 μM) in the ADP-stimulated state [[OXPHOS]]. 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. Any impairment of oxygen delivery, therefore, induces oxyconformance. In addition, a shift of mitochondrial oxygen kinetics to the right, particularly by competitive inhibition of CIV by NO, causes a further depression of respiration and a compensatory increase of local oxygen pressure. Above 1 kPa, mitochondrial oxygen uptake increases above hyperbolic saturation, which is probably due to oxygen radical production rather than the kinetics of CIV. In cultured cells, the pronounced oxygen uptake above mitochondrial saturation at air-level oxygen pressure cannot be inhibited by rotenone and antimycin A, amounting to > 20% of [[ROUTINE respiration]] in fibroblasts. Biochemical models of oxyconformance of CIV are evaluated relative to patterns of intracellular oxygen distribution in the tissue and enzyme turnover ''in vivo'', considering the kinetic effects of CIV excess capacity on flux through the mitochondrial electron transfer system.
|keywords=Oxygen kinetics, Cytochrome c oxidase, Mitochondrial respiratory control, Oxygen limitation, Hypoxia
|keywords=Oxygen kinetics, Cytochrome c oxidase, Mitochondrial respiratory control, Oxygen limitation, Hypoxia
|mipnetlab=AT_Innsbruck_Gnaiger E, AT Innsbruck MitoCom
|mipnetlab=AT Innsbruck Gnaiger E
|discipline=Mitochondrial Physiology
}}
}}
== Cited by ==
::* 30 articles in PubMed (2023-01-17) https://pubmed.ncbi.nlm.nih.gov/14713113/
{{Template:Cited by Gnaiger 2020 BEC MitoPathways}}
{{Template:Cited by Komlodi 2021 MitoFit AmR-O2}}
{{Template:Cited by Komlodi 2022 MitoFit ROS review}}
== Updated terminology ==
::::* Reference: Gnaiger E et al ― MitoEAGLE Task Group (2020) Mitochondrial physiology. Bioenerg Commun 2020.1. [[doi:10.26124/bec:2020-0001.v1]]
::::
{| class="wikitable"
|+ Caption text
|-
! Term !! Updated (2020) !! Publication (2003)
|-
| cytochrome ''c'' oxidase || CIV || COX
|-
| CI || [[Complex I]] || complex I
|-
| ''R'' || [[ROUTINE respiration]] || routine respiration
|-
| ''P''  || [[OXPHOS]] || [[State 3]]
|-
| ETS || [[electron transfer system]] || electron transport chain
|-
| ''Rox'' || [[residual oxygen consumption]] || non-COX respiration
|-
|  || [[noncoupled]] || uncoupled
|-
| amol·s<sup>-1</sup>·x<sup>-1</sup> || pmol·s<sup>-1</sup>·Mx<sup>-1</sup> || pmol·s<sup>-1</sup>·10<sup>-6</sup> cells
|-
| O2k || Oroboros [[Oxygraph-2k]] || OROBOROS Oxygraph
|-
| mtIM || mitochondrial inner membrane || inner mitochondrial membrane
|}
== Correction ==
::::* A synkinetic systems approach is required to explain tissue-specific differences in mitochondrial oxygen affinity, which is a function of the properties of the electron transport {''transfer''} pathway [25, 26]. The excess capacity of COX {CIV} ensures that this enzyme operates far from its limiting turnover capacity even at maximum activity of the respiratory chain {''system''}. When the excess capacity of COX {CIV} is reduced, then COX {CIV} is pushed to increasing turnover at identical rates of mitochondrial respiration. As a consequence, the mitochondrial ''p''<sub>50</sub> declines {'''''Correction''''': The oxygen affinity declines, but the mitochondrial ''p''<sub>50</sub> increases instead of declining}. Downregulation of cytochrome ''c'' oxidase activity, therefore, increases the degree of oxyconformance in the low-oxygen range (Figure 1).
== Selected quotes ==
::::* 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. In contrast, various degrees of oxyconformance are observed in cells [2, 9, 28, 33, 36]. Biochemical and physiological approaches are required to separate the primary kinetic mechanisms from secondary effects of oxygen sensing, signalling, gene expression and protein synthesis or degradation. Modern trends in mitochondrial bioenergetics integrate (''1'') molecular and enzyme kinetic properties of the membrane proteins constituting the [[electron transfer system]], particularly the proton pumps such as cytochrome ''c'' oxidase [70], (''2'') synkinetic properties of the mitochondrial metabolic network involved in the control of flux and energetic efficiency [26, 27], and (''3'') the regulatory role of mitochondrial signalling in the cell and of intracellular conditions in the tissue.
::::* Several apparent paradoxes have emerged in the physiology and pathology of hypoxia, such as the oxygen, lactate, efficiency, and diving paradoxes [32]. While some have been rationalized and solved, others remain hot spots of current research. Another apparent paradox on [[hypoxia]] arises in studies of the bioenergetics of isolated and cultured cells, where respiration, contractile performance or protein synthesis are apparently oxygen limited at partial pressures at or above normoxic tissue levels. Such extended oxygen conformance deviates from the “regulatory” pattern or oxygen independence of mitochondrial respiration to <1 kPa (7.5 mmHg [28]).
::::* Compared with ambient oxygen pessure of 20 kPa (150 mmHg), oxygen levels are low within active tissues and are under tight control by microcirculatory adjustments to match oxygen supply and demand. Alveolar normoxia of 13 kPa (100 mmHg) contrasts with a corresponding 1 to 5 kPa (10 to 40 mmHg) extracellular ''p''<sub>O<sub>2</sub></sub> in solid organs such as heart, brain, kidney and liver [19].
::::* .. respiration inhibited by antimycin A and particularly by cyanide cannot simply be interpreted as non-mitochondrial respiration. Caution is required since cyanide is not specific for cytochrome ''c'' oxidase but is a direct inhibitor of other oxidases, such as urate oxidase [56] and inhibits the heme-containing catalase [20].
::::* Diffusion limitation is further aggravated in permeabilized fiber bundles with a radius of 35 up to 200 µm [38, 52]. For comparison, 200 µm away from the nearest blood vessel, the ''p''<sub>O<sub>2</sub></sub> drops from 1.9 kPa (14 mmHg) to zero in tumors with relatively low aerobic capacity [30].
::::* Relative to isolated mitochondria, a staggering 100-fold increase of the extracellular ''p''<sub>50</sub> is measured in heavily stirred permeabilized fiber bundles prepared from rat heart and soleus muscle [39], in which case oxyconformance extends up to air saturation in terms of a monophasic hyperbolic oxygen dependence (Fig. 6).
::::* Increased diffusion distances are in line with the distinct kinetic responses to external oxygen, when highly oxygen-independent fibroblasts and endothelial cells are compared with oxyconforming cardiomyocytes and fiber bundles (Figs. 4 and 6), spanning a 0.1·10<sup>6</sup>-fold volume range (Table 1).
::::* It remains to be defined, how low the ''p''<sub>O<sub>2</sub></sub> needs to be set in the incubation medium to provide a “normoxic” environment for embryonic cardiomyocytes.
::::* The adaptive mechanisms of metabolic downregulation in hypometabolic states of hypoxia [31], however, are more clearly appreciated by relating physiological and biochemical control mechanisms to the diversity of oxygen regimes and metabolic challenges met by various types of mitochondria, cells, tissues and organisms.
{{Template:Keywords: hypoxia, normoxia, hyperoxia}}
{{Labeling
{{Labeling
|area=Respiration
|organism=Human, Rat
|tissues=Heart, Liver, Endothelial;epithelial;mesothelial cell, Fibroblast
|preparations=Permeabilized cells, Permeabilized tissue, Isolated mitochondria, Oxidase;biochemical oxidation, Intact cells
|topics=Oxygen kinetics
|couplingstates=ROUTINE, OXPHOS
|pathways=N, ROX
|instruments=Oxygraph-2k
|instruments=Oxygraph-2k
|injuries=Hypoxia
|additional=Tissue normoxia,  
|organism=Human, Rat
BEC 2020.2, MitoFit 2021 AmR-O2, MitoFit2022Hypoxia, MitoFit 2022 ROS review
|tissues=Cardiac muscle, Fibroblast, Hepatocyte; Liver, Endothelial; Epithelial; Mesothelial Cell
|preparations=Intact Cell; Cultured; Primary, Permeabilized cells, Permeabilized tissue, Isolated Mitochondria, Oxidase; Biochemical Oxidation
|couplingstates=OXPHOS
|kinetics=Oxygen
|discipline=Mitochondrial Physiology
}}
}}
[http://www.oroboros.at/fileadmin/user_upload/O2k-Publications/Gnaiger_2003_Adv_Exp_Med_Biol.pdf pdf]

Latest revision as of 03:42, 17 January 2023

Publications in the MiPMap
Has title::Gnaiger E (2003) Oxygen conformance of cellular respiration. A perspective of mitochondrial physiology. https://doi.org/10.1007/978-1-4419-8997-0_4

» [[Has info::Adv Exp Med Biol 543:39-55. PMID: 14713113]], [[Has info::Bioblast pdf]]

Was written by::Gnaiger Erich (Was published in year::2003) Was published in journal::Adv Exp Med Biol

Abstract: [[has abstract::Oxygen pressure declines from normoxic air-level to the microenvironment of mitochondria where cytochrome c oxidase (CIV) reduces oxygen to water at oxygen levels as low as 0.3 kPa (2 Torr; 3 μM; 1.5 % air saturation). Intracellular hypoxia is defined as (1) local oxygen pressure below normoxic reference states, or (2) limitation of mitochondrial respiration by oxygen levels below kinetic saturation, resulting in oxyconformance. High-resolution respirometry provides the methodology to measure mitochondrial and cellular oxygen kinetics in the relevant low oxygen range <1 kPa (7.5 mmHg; 9-10 μM; 5 % air saturation). Respiration of isolated heart mitochondria follows hyperbolic oxygen kinetics with half-saturating oxygen pressure, p50, of 0.04 kPa (0.3 Torr; 0.4 μM) in the ADP-stimulated state OXPHOS. 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. Any impairment of oxygen delivery, therefore, induces oxyconformance. In addition, a shift of mitochondrial oxygen kinetics to the right, particularly by competitive inhibition of CIV by NO, causes a further depression of respiration and a compensatory increase of local oxygen pressure. Above 1 kPa, mitochondrial oxygen uptake increases above hyperbolic saturation, which is probably due to oxygen radical production rather than the kinetics of CIV. In cultured cells, the pronounced oxygen uptake above mitochondrial saturation at air-level oxygen pressure cannot be inhibited by rotenone and antimycin A, amounting to > 20% of ROUTINE respiration in fibroblasts. Biochemical models of oxyconformance of CIV are evaluated relative to patterns of intracellular oxygen distribution in the tissue and enzyme turnover in vivo, considering the kinetic effects of CIV excess capacity on flux through the mitochondrial electron transfer system.]] • Keywords: has publicationkeywords::Oxygen kinetics, has publicationkeywords::Cytochrome c oxidase, has publicationkeywords::Mitochondrial respiratory control, has publicationkeywords::Oxygen limitation, has publicationkeywords::Hypoxia

• O2k-Network Lab: Was published by MiPNetLab::AT Innsbruck Gnaiger E

Cited by

Gnaiger 2020 BEC MitoPathways
Gnaiger E (2020) Mitochondrial pathways and respiratory control. An introduction to OXPHOS analysis. 5th ed. Bioenerg Commun 2020.2. https://doi.org/10.26124/bec:2020-0002


  • Komlódi T, Sobotka O, Gnaiger E (2021) Facts and artefacts on the oxygen dependence of hydrogen peroxide production using Amplex UltraRed. Bioenerg Commun 2021.4. https://doi:10.26124/BEC:2021-0004
  • Komlódi T, Gnaiger E (2022) Discrepancy on oxygen dependence of mitochondrial ROS production - review. MitoFit Preprints 2022 (in prep).

Updated terminology

Caption text
Term Updated (2020) Publication (2003)
cytochrome c oxidase CIV COX
CI Complex I complex I
R ROUTINE respiration routine respiration
P OXPHOS State 3
ETS electron transfer system electron transport chain
Rox residual oxygen consumption non-COX respiration
noncoupled uncoupled
amol·s-1·x-1 pmol·s-1·Mx-1 pmol·s-1·10-6 cells
O2k Oroboros Oxygraph-2k OROBOROS Oxygraph
mtIM mitochondrial inner membrane inner mitochondrial membrane

Correction

  • A synkinetic systems approach is required to explain tissue-specific differences in mitochondrial oxygen affinity, which is a function of the properties of the electron transport {transfer} pathway [25, 26]. The excess capacity of COX {CIV} ensures that this enzyme operates far from its limiting turnover capacity even at maximum activity of the respiratory chain {system}. When the excess capacity of COX {CIV} is reduced, then COX {CIV} is pushed to increasing turnover at identical rates of mitochondrial respiration. As a consequence, the mitochondrial p50 declines {Correction: The oxygen affinity declines, but the mitochondrial p50 increases instead of declining}. Downregulation of cytochrome c oxidase activity, therefore, increases the degree of oxyconformance in the low-oxygen range (Figure 1).


Selected quotes

  • 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. In contrast, various degrees of oxyconformance are observed in cells [2, 9, 28, 33, 36]. Biochemical and physiological approaches are required to separate the primary kinetic mechanisms from secondary effects of oxygen sensing, signalling, gene expression and protein synthesis or degradation. Modern trends in mitochondrial bioenergetics integrate (1) molecular and enzyme kinetic properties of the membrane proteins constituting the electron transfer system, particularly the proton pumps such as cytochrome c oxidase [70], (2) synkinetic properties of the mitochondrial metabolic network involved in the control of flux and energetic efficiency [26, 27], and (3) the regulatory role of mitochondrial signalling in the cell and of intracellular conditions in the tissue.
  • Several apparent paradoxes have emerged in the physiology and pathology of hypoxia, such as the oxygen, lactate, efficiency, and diving paradoxes [32]. While some have been rationalized and solved, others remain hot spots of current research. Another apparent paradox on hypoxia arises in studies of the bioenergetics of isolated and cultured cells, where respiration, contractile performance or protein synthesis are apparently oxygen limited at partial pressures at or above normoxic tissue levels. Such extended oxygen conformance deviates from the “regulatory” pattern or oxygen independence of mitochondrial respiration to <1 kPa (7.5 mmHg [28]).
  • Compared with ambient oxygen pessure of 20 kPa (150 mmHg), oxygen levels are low within active tissues and are under tight control by microcirculatory adjustments to match oxygen supply and demand. Alveolar normoxia of 13 kPa (100 mmHg) contrasts with a corresponding 1 to 5 kPa (10 to 40 mmHg) extracellular pO2 in solid organs such as heart, brain, kidney and liver [19].
  • .. respiration inhibited by antimycin A and particularly by cyanide cannot simply be interpreted as non-mitochondrial respiration. Caution is required since cyanide is not specific for cytochrome c oxidase but is a direct inhibitor of other oxidases, such as urate oxidase [56] and inhibits the heme-containing catalase [20].
  • Diffusion limitation is further aggravated in permeabilized fiber bundles with a radius of 35 up to 200 µm [38, 52]. For comparison, 200 µm away from the nearest blood vessel, the pO2 drops from 1.9 kPa (14 mmHg) to zero in tumors with relatively low aerobic capacity [30].
  • Relative to isolated mitochondria, a staggering 100-fold increase of the extracellular p50 is measured in heavily stirred permeabilized fiber bundles prepared from rat heart and soleus muscle [39], in which case oxyconformance extends up to air saturation in terms of a monophasic hyperbolic oxygen dependence (Fig. 6).
  • Increased diffusion distances are in line with the distinct kinetic responses to external oxygen, when highly oxygen-independent fibroblasts and endothelial cells are compared with oxyconforming cardiomyocytes and fiber bundles (Figs. 4 and 6), spanning a 0.1·106-fold volume range (Table 1).
  • It remains to be defined, how low the pO2 needs to be set in the incubation medium to provide a “normoxic” environment for embryonic cardiomyocytes.
  • The adaptive mechanisms of metabolic downregulation in hypometabolic states of hypoxia [31], however, are more clearly appreciated by relating physiological and biochemical control mechanisms to the diversity of oxygen regimes and metabolic challenges met by various types of mitochondria, cells, tissues and organisms.


Keywords: Oxia terms

Questions.jpg


Click to expand or collaps
Bioblast links: Hypoxia, normoxia, hyperoxia - >>>>>>> - Click on [Expand] or [Collapse] - >>>>>>>

{{#ask:Additional label::MitoPedia:Normoxia | mainlabel=Term |?Has abbr=Abbreviation |?Description=Description |format=broadtable |limit=5000 |order=ascending }}

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

{{#ask:Additional label::Tissue normoxia |?Was published in year=Year |?Has title=Reference |?Mammal and model=Organism |?Tissue and cell=Tissue;cell |?Preparation=Preparations |?Stress |?Diseases |format=broadtable |limit=5000 |offset=0 |sort=Was published in year |order=descending }}

Abstracts: Tissue normoxia

{{#ask: Additional label::Tissue normoxia |?Was submitted in year=Year |?Has title=Reference |?Mammal and model=Organism |?Tissue and cell=Tissue;cell |?Preparation=Preparations |?Stress |?Diseases |format=broadtable |limit=5000 |offset=0 |sort=Was submitted in year |order=descending }}



Labels: MiParea: MiP area::Respiration 


Organism: Organism::Human, Organism::Rat  Tissue;cell: tissue and cell::Heart, tissue and cell::Liver, tissue and cell::Endothelial;epithelial;mesothelial cell, tissue and cell::Fibroblast  Preparation: Preparation::Permeabilized cells, Preparation::Permeabilized tissue, Preparation::Isolated mitochondria, Preparation::Oxidase;biochemical oxidation, Preparation::Intact cells 

Regulation: Topic::Oxygen kinetics  Coupling state: Coupling states::ROUTINE, Coupling states::OXPHOS  Pathway: Pathways::N, Pathways::ROX  HRR: Instrument and method::Oxygraph-2k 

additional label::Tissue normoxia, additional label::BEC 2020.2, additional label::MitoFit 2021 AmR-O2, additional label::MitoFit2022Hypoxia, additional label::MitoFit 2022 ROS review 

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