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Regulation of Cellular Gas Exchange, Oxygen Sensing, and Metabolic Control

T. L. Clanton, M. C. Hogan, L. B. Gladden

10.1002/cphy.c120030

Source: Volume 3, Issue 3, July 2013

Published online: July 2013

Full Article on Wiley Online Library



Abstract

Cells must continuously monitor and couple their metabolic requirements for ATP utilization with their ability to take up O2 for mitochondrial respiration. When O2 uptake and delivery move out of homeostasis, cells have elaborate and diverse sensing and response systems to compensate. In this review, we explore the biophysics of O2 and gas diffusion in the cell, how intracellular O2 is regulated, how intracellular O2 levels are sensed and how sensing systems impact mitochondrial respiration and shifts in metabolic pathways. Particular attention is paid to how O2 affects the redox state of the cell, as well as the NO, H2S, and CO concentrations. We also explore how these agents can affect various aspects of gas exchange and activate acute signaling pathways that promote survival. Two kinds of challenges to gas exchange are also discussed in detail: when insufficient O2 is available for respiration (hypoxia) and when metabolic requirements test the limits of gas exchange (exercising skeletal muscle). This review also focuses on responses to acute hypoxia in the context of the original “unifying theory of hypoxia tolerance” as expressed by Hochachka and colleagues. It includes discourse on the regulation of mitochondrial electron transport, metabolic suppression, shifts in metabolic pathways, and recruitment of cell survival pathways preventing collapse of membrane potential and nuclear apoptosis. Regarding exercise, the issues discussed relate to the O2 sensitivity of metabolic rate, O2 kinetics in exercise, and influences of available O2 on glycolysis and lactate production. © 2013 American Physiological Society. Compr Physiol 3:1135‐1190, 2013.

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Figure 1. Figure 1.

Graphical representation of a simplified diffusion equation, in its simplest form, based on Ohm's law. The resistances to diffusion (R = inverse of conductance, G) can be summed from the source of the O2 gradient in the capillary (PcO2) to the surface of the cell (PsO2) or from the PsO2 to the intracellular environment (PiO2). The flow of O2 () is analogous to current. See text for details.
Figure 2. Figure 2.

Typical diffusion barriers between the extracellular fluid and the mitochondria. Approximate values for diffusion coefficients (D in cm2·s−1) for each medium are listed. See text for details and Table 2 for sources of D.
Figure 3. Figure 3.

Theoretical diffusion coefficients and solubilities for O2 and CO2 across the plasma membrane. Values and trajectories are based largely on molecular modeling studies of Wang et al. (541). Notably the polar head groups of the bilayer membrane impose a diffusion barrier at least as great as the unstirred layer of the cytosol. Whereas the original model (541) used homogeneous aqueous phase on both sides of the bilayer, the illustration assumes a typical cytosolic diffusion constants for CO2 and O2 from Table 2. The graphical representation of the bilayer model and the CO2 molecules are also from Wang et al. (541).
Figure 4. Figure 4.

Graphical representation of the theoretical role of membranes as conduits for distribution of O2 and other gases. The membrane has the characteristic of an RC circuit resulting in “cable”‐like characteristics for O2 transport and transport of other gases. The extracellular space acts as a conduit as well, with a low resistance to diffusion, but also a low capacitance for O2 storage. The cytosol (in the absence of myoglobin or other O2 carrying molecules) is a region of high resistance and low capacitance. It is possible that such conductive properties of the membrane could provide an avenue for O2 delivery into the core of striated muscle fibers via T‐tubular structures.
Figure 5. Figure 5.

Electron micrographs from rat diaphragm muscle: (1) left and right, the close association of the T tubules and sarcoplasmic reticular membranes at the triad with the reticular mitochondrial network. (2) Right shows the high density of subsarcolemmal mitochondria, very close to the extracellular space. (3) Right extracellular space. Such an arrangement avoids the barrier for diffusion presented by the cytosol. (4) Right myonucleus surrounded by mitochondria, a typical kind of mitochondrial clustering seen in skeletal muscle.
Figure 6. Figure 6.

The role of CO2 hydration in the transport of CO2 across the membrane. The high concentration of HCO3− in the cytosol and the membrane‐associated activity of carbonic anhydrase (CA) ensure a high concentration of CO2 at the membrane region, within the unstirred layer, reducing the gradients across the cytosol, which has a relatively low diffusion constant. This distributed mechanism also supports H+ transport (outlined in red) through formation and diffusion of CO2.
Figure 7. Figure 7.

Changes in prolyl hydroxylase (PHD) activity as a function of [O2]. Early experiments suggested PHD had a very low sensitivity to O2 (216) but more recent experiments from ex vivo preparations (34) have shown the O2 sensitivity of PHD to be more in a range compatible with its known in vivo effects on HIF‐1α (see text for details).
Figure 8. Figure 8.

The interdependent redox pathways believed to be important in normal control of NOX enzymes in a typical cell containing NOX2 and NOX4. Note the close association between oxidant production, thiol redox status, and redox cycling in the continued formation of NOX. In conditions of sufficient O2 as a substrate, redox status of NADH and NADPH can be a controlling influence on ROS production via NOX isoforms. See text for details.
Figure 9. Figure 9.

Gas‐sensing systems influenced by available [O2]. (A) The signaling pathways involved with production of H2S in hypoxia and its intracellular targets. CSE, cystathionine γ‐lyase; CBS, cystathionine β‐lyase; T‐(SH)2, thioredoxin; CcO, cytochrome C oxidase; sGC, soluble guanylate cyclase. Note the primary effect of O2 is on the rate of H2S degradation in the mitochondria. (B) The sources of molecular NO and its degradation during changes in O2 in the microenvironment. Elevations in O2 contribute to NO degradation and compete with other reactive sites for NO degradation such as myoglobin. Moderate decreases in O2 reduce the rate of NO formation but severe decreases in O2 decrease the rate of degradation and make other sources of NO available, such as from enzymatic conversion of nitrite (NO2−) to NO. The effects on membrane channel behavior are largely cytoprotective. (C) The primary signaling pathways for carbon monoxide (CO) formation and the possible targets in hypoxia. The heme‐oxygenase enzyme is not particularly O2 sensitive but the ability of CO to influence regulatory enzymes is enhanced in hypoxia as it is better able to compete with other reactants such as NO and O2 for hemes and other metal centers.
Figure 10. Figure 10.

Changes in the redox behavior of redox metabolites and sensor systems as a function of cellular O2 availability. (A) Expected changes in NADH and NADPH redox state. The dotted versus solid line for NADPH reflects different responses in different cell types, as discussed in the text. (B) Expected changes in NO, ROS, CO, and H2S as a function of O2 availability. (C) Approximate reaction rates of various O2 sensing systems in the cell that reflect how the integrated system might work over a wide range of O2 exposures. See text for details.
Figure 11. Figure 11.

An integrated hydraulic model of factors affecting the redox behavior of NADH and NADPH. Top are the reduced forms (red) and below the oxidized forms (blue) of each pyridine nucleotide. Changes in the available pool of glucose‐6‐phosphate (G6‐P) have a strong influence on NADPH and NADP, but their proportional concentrations depend on the relative strengths of the pentose pathway versus the glycolytic pathway in a given situation, which compete for G6‐P. The relative oxidation of each reduced form depends on the competing reactions below, which represent pathways for loss of reduced forms of NADH or NADPH in conditions of hypoxia. Blockers of any reactions in the system can have major influences on the overall redox behavior and the amount of ROS formed in different O2 environments. See text for details.
Figure 12. Figure 12.

A summary of the primary strategies cells use to combat gas exchange challenges such as in hypoxia (see text for details).
Figure 13. Figure 13.

Inhibition of respiratory rates in isolated mitochondria as a function of NO. Blue line: the effects of varying [NO] in 90 μmol/L [O2] versus red line: the effects of varying [NO] at 10 μmol/L [O2]. Note the elevated sensitivity to NO in hypoxia. Redrawn, with permission, from reports by Aguirre et al. (3).
Figure 14. Figure 14.

Behavior of mitochondrial respiration in hypoxia. (A) Theoretical effects of elevated [ADP] (or Pi, not shown) on the rate of respiration at submaximal levels of oxygen consumption. Though shifts in Km may occur hypoxia as discussed later in the review, they are not needed for this to be an effective mechanism for raising the gradient for O2 diffusion and raising . (B) Effects of hypoxia on the efficiency (ADP flux/O2), as a function of respiratory rate. In very severe hypoxia (red dot) there is a marked deviation of the curve that exhibits recruitment of mechanisms improving efficiency. Redrawn, with permission, from data in (164).
Figure 15. Figure 15.

The effects of state‐dependent allosteric ATP/ADP control of cytochrome C oxidase. (A) Cells in vivo are believed to operate in a phosphorylated state that maintains membrane potential and low levels of ROS production at a lower membrane potential ψm. (B) When ADP is elevated in response to increases in metabolism, the ψm does not depolarize as would be predicted by classic control theory. (C) In unphosphorylated mitochondria, as would occur in isolated mitochondrial experiments, the ψm is very high, unresponsive to ATP/ADP, with a greater degree of uncoupling and ROS formation. (D) When ADP rises in this state, ψm decreases, which drives the respiratory chain and results in greater consumption of O2 by classic control theory (see text for details).
Figure 16. Figure 16.

Metabolic suppression in animal species of different size in response to hypoxia exposure. Changes in (A) , (B) core temperature, and (C) respiratory exchange ratio (R) are more evident in small animals in response to acute exposure to 10% O2. In all experiments a steady state in gas exchange was achieved prior to measurements. Original data, with permission, from Frappell et al. (139).
Figure 17. Figure 17.

Schematic of a typical oxygen uptake ()‐availability (PO2) relationship in normal cells experiencing acute hypoxia (A‐C), cells exhibiting metabolic suppression (curve D) and the presumed response to irreversible hypoxic injury (curve E). Dashed line would correspond to a theoretical normal resting PiO2, which would predictably vary between cell types. Presumably as severe hypoxia progresses over time, cells would go through a transition from normal acute responses (A‐C) to and adapted response (curves D) and eventually to injury (curve E). See text for details.
Figure 18. Figure 18.

Acute ion channel responses to hypoxia. (A) Changes in outward K+ current of a typical voltage‐dependent Kv channel in previously depolarized cells in normoxia to relative hypoxia (120‐14 Torr), obtained by permission from Osipenko et al. (385). (B) Elevations in slow inward Na+ current in response to hypoxia in inside out patches of hippocampal cells. PO2 dropped from 130 to 30 Torr. TTX = tetrodotoxin, a Na+ channel poison, used with permission from Hammarstom et al. (193).
Figure 19. Figure 19.

Pulmonary artery smooth muscle responses to hypoxia. (A) Schematic of the normal state of O2 sensitive pulmonary arterial smooth muscle cells. In high PO2, considerable ROS (most likely from NOX or mitochondria) is produced, which functions to maintain the K+ channels in an “open” position. This keeps membrane potential close to the K+ equilibrium potential. These conditions are shown on a classic voltage diagram on the right. (B) In conditions in alveolar hypoxia, ROS production by NOX, and/or mitochondria is diminished. This leaves the K+ channels with a higher probability of closing. Loss of outward positive current, results in a loss of membrane potential, Vm. Depolarization induces Ca+2 entry via voltage‐dependent (L‐type) Ca+2 channels. See text for details.
Figure 20. Figure 20.

Autocrine/paracrine pathways for cellular protection in hypoxia. Two primary pathways recruit cellular salvage and cytoprotective signaling pathways. Both depend on secreted metabolites, cytokines, or other factors produced during hypoxic exposure. See text for details.
Figure 21. Figure 21.

The primary effector pathways of SAFE and RISK autocrine/paracrine signaling. See text for details.
Figure 22. Figure 22.

Measurements of PiO2 versus work rate using combined data of Molé et al. (352); (solid squares) and Richardson et al. (427) (solid circles). Resting data from Richardson, in Carlier's lab (424). Note that the reported PiO2 value at 100% of was the same for both data sets; therefore, the square is overlying the circle at this point.
Figure 23. Figure 23.

Predicted dependence of mitochondrial O2 consumption on PO2 at high and low energy states. (A) Data based on the mathematical models of Wilson (564). (B) Data based on work done by Gnaiger and colleagues, as reviewed in (160,450). Note that the two models differ in the direction of shifts in the Km for O2 in different energy states and the greater O2 sensitivity in B. See text for details.
Figure 24. Figure 24.

Changes in intracellular PO2 (PiO2) in single muscle fibers as a function metabolic rate. Responses were induced by different relative durations of contraction (200 or 400 ms) and fixed relaxation time. Though PiO2 fell faster with greater metabolic activities, the relative rate of fall was unchanged.
Figure 25. Figure 25.

Relative changes in NADH autofluorescence in Xenopus isolated single skeletal muscle fibers (n = 6). Measurements made during steady‐state contractions at high (30 Torr) and low (0‐2 Torr) extracellular PO2.
Figure 26. Figure 26.

Relative changes in NADH fluorescence in the outer 10% versus the center 10% of Xenopus isolated single skeletal muscle fibers (n = 6). Measurements made during steady‐state contractions at extracellular PO2 = 30 Torr. The NADH fluorescence at the 1‐min time point (but not at 2 min) was significantly greater in the cell core versus the cell periphery (outer).
Figure 27. Figure 27.

Hypothetical effect of O2 dependence of metabolism during transition from one exercise work rate to another. With increase in work rate (arrow 1), [ADP]·[Pi]/[ATP] increases. However, intracellular PO2 may also decrease with increased work rate (arrow 2). As a result, O2 uptake would transiently be insufficient to supply ATP at the required rate, leading to a further increase in [ADP]·[Pi]/[ATP] (bracket 3, from open circle to solid square) for adequate stimulation of oxidative phosphorylation. The connection to La− metabolism is that the increases in [ADP]·[Pi]/[ATP] stimulate simultaneous elevations in glycolysis and therefore La− production, See text for details.


Figure 1.

Graphical representation of a simplified diffusion equation, in its simplest form, based on Ohm's law. The resistances to diffusion (R = inverse of conductance, G) can be summed from the source of the O2 gradient in the capillary (PcO2) to the surface of the cell (PsO2) or from the PsO2 to the intracellular environment (PiO2). The flow of O2 () is analogous to current. See text for details.



Figure 2.

Typical diffusion barriers between the extracellular fluid and the mitochondria. Approximate values for diffusion coefficients (D in cm2·s−1) for each medium are listed. See text for details and Table 2 for sources of D.



Figure 3.

Theoretical diffusion coefficients and solubilities for O2 and CO2 across the plasma membrane. Values and trajectories are based largely on molecular modeling studies of Wang et al. (541). Notably the polar head groups of the bilayer membrane impose a diffusion barrier at least as great as the unstirred layer of the cytosol. Whereas the original model (541) used homogeneous aqueous phase on both sides of the bilayer, the illustration assumes a typical cytosolic diffusion constants for CO2 and O2 from Table 2. The graphical representation of the bilayer model and the CO2 molecules are also from Wang et al. (541).



Figure 4.

Graphical representation of the theoretical role of membranes as conduits for distribution of O2 and other gases. The membrane has the characteristic of an RC circuit resulting in “cable”‐like characteristics for O2 transport and transport of other gases. The extracellular space acts as a conduit as well, with a low resistance to diffusion, but also a low capacitance for O2 storage. The cytosol (in the absence of myoglobin or other O2 carrying molecules) is a region of high resistance and low capacitance. It is possible that such conductive properties of the membrane could provide an avenue for O2 delivery into the core of striated muscle fibers via T‐tubular structures.



Figure 5.

Electron micrographs from rat diaphragm muscle: (1) left and right, the close association of the T tubules and sarcoplasmic reticular membranes at the triad with the reticular mitochondrial network. (2) Right shows the high density of subsarcolemmal mitochondria, very close to the extracellular space. (3) Right extracellular space. Such an arrangement avoids the barrier for diffusion presented by the cytosol. (4) Right myonucleus surrounded by mitochondria, a typical kind of mitochondrial clustering seen in skeletal muscle.



Figure 6.

The role of CO2 hydration in the transport of CO2 across the membrane. The high concentration of HCO3− in the cytosol and the membrane‐associated activity of carbonic anhydrase (CA) ensure a high concentration of CO2 at the membrane region, within the unstirred layer, reducing the gradients across the cytosol, which has a relatively low diffusion constant. This distributed mechanism also supports H+ transport (outlined in red) through formation and diffusion of CO2.



Figure 7.

Changes in prolyl hydroxylase (PHD) activity as a function of [O2]. Early experiments suggested PHD had a very low sensitivity to O2 (216) but more recent experiments from ex vivo preparations (34) have shown the O2 sensitivity of PHD to be more in a range compatible with its known in vivo effects on HIF‐1α (see text for details).



Figure 8.

The interdependent redox pathways believed to be important in normal control of NOX enzymes in a typical cell containing NOX2 and NOX4. Note the close association between oxidant production, thiol redox status, and redox cycling in the continued formation of NOX. In conditions of sufficient O2 as a substrate, redox status of NADH and NADPH can be a controlling influence on ROS production via NOX isoforms. See text for details.



Figure 9.

Gas‐sensing systems influenced by available [O2]. (A) The signaling pathways involved with production of H2S in hypoxia and its intracellular targets. CSE, cystathionine γ‐lyase; CBS, cystathionine β‐lyase; T‐(SH)2, thioredoxin; CcO, cytochrome C oxidase; sGC, soluble guanylate cyclase. Note the primary effect of O2 is on the rate of H2S degradation in the mitochondria. (B) The sources of molecular NO and its degradation during changes in O2 in the microenvironment. Elevations in O2 contribute to NO degradation and compete with other reactive sites for NO degradation such as myoglobin. Moderate decreases in O2 reduce the rate of NO formation but severe decreases in O2 decrease the rate of degradation and make other sources of NO available, such as from enzymatic conversion of nitrite (NO2−) to NO. The effects on membrane channel behavior are largely cytoprotective. (C) The primary signaling pathways for carbon monoxide (CO) formation and the possible targets in hypoxia. The heme‐oxygenase enzyme is not particularly O2 sensitive but the ability of CO to influence regulatory enzymes is enhanced in hypoxia as it is better able to compete with other reactants such as NO and O2 for hemes and other metal centers.



Figure 10.

Changes in the redox behavior of redox metabolites and sensor systems as a function of cellular O2 availability. (A) Expected changes in NADH and NADPH redox state. The dotted versus solid line for NADPH reflects different responses in different cell types, as discussed in the text. (B) Expected changes in NO, ROS, CO, and H2S as a function of O2 availability. (C) Approximate reaction rates of various O2 sensing systems in the cell that reflect how the integrated system might work over a wide range of O2 exposures. See text for details.



Figure 11.

An integrated hydraulic model of factors affecting the redox behavior of NADH and NADPH. Top are the reduced forms (red) and below the oxidized forms (blue) of each pyridine nucleotide. Changes in the available pool of glucose‐6‐phosphate (G6‐P) have a strong influence on NADPH and NADP, but their proportional concentrations depend on the relative strengths of the pentose pathway versus the glycolytic pathway in a given situation, which compete for G6‐P. The relative oxidation of each reduced form depends on the competing reactions below, which represent pathways for loss of reduced forms of NADH or NADPH in conditions of hypoxia. Blockers of any reactions in the system can have major influences on the overall redox behavior and the amount of ROS formed in different O2 environments. See text for details.



Figure 12.

A summary of the primary strategies cells use to combat gas exchange challenges such as in hypoxia (see text for details).



Figure 13.

Inhibition of respiratory rates in isolated mitochondria as a function of NO. Blue line: the effects of varying [NO] in 90 μmol/L [O2] versus red line: the effects of varying [NO] at 10 μmol/L [O2]. Note the elevated sensitivity to NO in hypoxia. Redrawn, with permission, from reports by Aguirre et al. (3).



Figure 14.

Behavior of mitochondrial respiration in hypoxia. (A) Theoretical effects of elevated [ADP] (or Pi, not shown) on the rate of respiration at submaximal levels of oxygen consumption. Though shifts in Km may occur hypoxia as discussed later in the review, they are not needed for this to be an effective mechanism for raising the gradient for O2 diffusion and raising . (B) Effects of hypoxia on the efficiency (ADP flux/O2), as a function of respiratory rate. In very severe hypoxia (red dot) there is a marked deviation of the curve that exhibits recruitment of mechanisms improving efficiency. Redrawn, with permission, from data in (164).



Figure 15.

The effects of state‐dependent allosteric ATP/ADP control of cytochrome C oxidase. (A) Cells in vivo are believed to operate in a phosphorylated state that maintains membrane potential and low levels of ROS production at a lower membrane potential ψm. (B) When ADP is elevated in response to increases in metabolism, the ψm does not depolarize as would be predicted by classic control theory. (C) In unphosphorylated mitochondria, as would occur in isolated mitochondrial experiments, the ψm is very high, unresponsive to ATP/ADP, with a greater degree of uncoupling and ROS formation. (D) When ADP rises in this state, ψm decreases, which drives the respiratory chain and results in greater consumption of O2 by classic control theory (see text for details).



Figure 16.

Metabolic suppression in animal species of different size in response to hypoxia exposure. Changes in (A) , (B) core temperature, and (C) respiratory exchange ratio (R) are more evident in small animals in response to acute exposure to 10% O2. In all experiments a steady state in gas exchange was achieved prior to measurements. Original data, with permission, from Frappell et al. (139).



Figure 17.

Schematic of a typical oxygen uptake ()‐availability (PO2) relationship in normal cells experiencing acute hypoxia (A‐C), cells exhibiting metabolic suppression (curve D) and the presumed response to irreversible hypoxic injury (curve E). Dashed line would correspond to a theoretical normal resting PiO2, which would predictably vary between cell types. Presumably as severe hypoxia progresses over time, cells would go through a transition from normal acute responses (A‐C) to and adapted response (curves D) and eventually to injury (curve E). See text for details.



Figure 18.

Acute ion channel responses to hypoxia. (A) Changes in outward K+ current of a typical voltage‐dependent Kv channel in previously depolarized cells in normoxia to relative hypoxia (120‐14 Torr), obtained by permission from Osipenko et al. (385). (B) Elevations in slow inward Na+ current in response to hypoxia in inside out patches of hippocampal cells. PO2 dropped from 130 to 30 Torr. TTX = tetrodotoxin, a Na+ channel poison, used with permission from Hammarstom et al. (193).



Figure 19.

Pulmonary artery smooth muscle responses to hypoxia. (A) Schematic of the normal state of O2 sensitive pulmonary arterial smooth muscle cells. In high PO2, considerable ROS (most likely from NOX or mitochondria) is produced, which functions to maintain the K+ channels in an “open” position. This keeps membrane potential close to the K+ equilibrium potential. These conditions are shown on a classic voltage diagram on the right. (B) In conditions in alveolar hypoxia, ROS production by NOX, and/or mitochondria is diminished. This leaves the K+ channels with a higher probability of closing. Loss of outward positive current, results in a loss of membrane potential, Vm. Depolarization induces Ca+2 entry via voltage‐dependent (L‐type) Ca+2 channels. See text for details.



Figure 20.

Autocrine/paracrine pathways for cellular protection in hypoxia. Two primary pathways recruit cellular salvage and cytoprotective signaling pathways. Both depend on secreted metabolites, cytokines, or other factors produced during hypoxic exposure. See text for details.



Figure 21.

The primary effector pathways of SAFE and RISK autocrine/paracrine signaling. See text for details.



Figure 22.

Measurements of PiO2 versus work rate using combined data of Molé et al. (352); (solid squares) and Richardson et al. (427) (solid circles). Resting data from Richardson, in Carlier's lab (424). Note that the reported PiO2 value at 100% of was the same for both data sets; therefore, the square is overlying the circle at this point.



Figure 23.

Predicted dependence of mitochondrial O2 consumption on PO2 at high and low energy states. (A) Data based on the mathematical models of Wilson (564). (B) Data based on work done by Gnaiger and colleagues, as reviewed in (160,450). Note that the two models differ in the direction of shifts in the Km for O2 in different energy states and the greater O2 sensitivity in B. See text for details.



Figure 24.

Changes in intracellular PO2 (PiO2) in single muscle fibers as a function metabolic rate. Responses were induced by different relative durations of contraction (200 or 400 ms) and fixed relaxation time. Though PiO2 fell faster with greater metabolic activities, the relative rate of fall was unchanged.



Figure 25.

Relative changes in NADH autofluorescence in Xenopus isolated single skeletal muscle fibers (n = 6). Measurements made during steady‐state contractions at high (30 Torr) and low (0‐2 Torr) extracellular PO2.



Figure 26.

Relative changes in NADH fluorescence in the outer 10% versus the center 10% of Xenopus isolated single skeletal muscle fibers (n = 6). Measurements made during steady‐state contractions at extracellular PO2 = 30 Torr. The NADH fluorescence at the 1‐min time point (but not at 2 min) was significantly greater in the cell core versus the cell periphery (outer).



Figure 27.

Hypothetical effect of O2 dependence of metabolism during transition from one exercise work rate to another. With increase in work rate (arrow 1), [ADP]·[Pi]/[ATP] increases. However, intracellular PO2 may also decrease with increased work rate (arrow 2). As a result, O2 uptake would transiently be insufficient to supply ATP at the required rate, leading to a further increase in [ADP]·[Pi]/[ATP] (bracket 3, from open circle to solid square) for adequate stimulation of oxidative phosphorylation. The connection to La− metabolism is that the increases in [ADP]·[Pi]/[ATP] stimulate simultaneous elevations in glycolysis and therefore La− production, See text for details.

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Article Title: Regulation of Cellular Gas Exchange, Oxygen Sensing, and Metabolic Control
 

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T. L. Clanton, M. C. Hogan, L. B. Gladden. Regulation of Cellular Gas Exchange, Oxygen Sensing, and Metabolic Control. Compr Physiol 2013, 3: 1135-1190. doi: 10.1002/cphy.c120030