Bioenergetics at low oxygen: dependence of respiration and phosphorylation on oxygen and adenosine diphosphate supply

Oxygen limitation is generally considered as impairment of mitochondrial respiration under hypoxia and ischemia. Low intracellular oxygen levels under normoxia, however, imply mild oxygen limitation, provide protection from oxidative stress, and result from economical strategies for oxygen transport through the respiratory cascade to cytochrome c oxidase. Both perspectives relate to the critical oxygen pressure, which inhibits mitochondrial respiration. Based on methodological considerations of oxygen kinetics and a presentation of high-resolution respirometry, mitochondrial oxygen affinities (1/P₅₀) are reviewed with particular emphasis on the turnover effect under control of adenosine diphosphate ADP concentration, which increases the P₅₀ in active states. ADP/O₂ flux ratios are high even under severe oxygen limitation, as demonstrated by calorespirometry. Oxygen limitation reduces the uncoupled respiration observed under control by ADP, as shown by relationships derived between ADP/O₂ flux ratios, respiratory control ratios, and ADP kinetics. Bioenergetics at low oxygen versus oxidative stress must be considered in the context of limitation of maximum aerobic activity, ischemia-reperfusion injury, mitochondrial signalling to apoptosis, and mitochondrial theories of ageing.