Control of mitochondrial and cellular respiration by oxygen

Control and regulation of mitochondrial and cellular respiration by oxygen is discussed with three aims: (1) A review of intracellular oxygen levels and gradients, particularly in heart, emphasizes the dominance of extracellular oxygen gradients. Intracellular oxygen pressure, p(O2) is low, typically one to two orders of magnitude below incubation conditions used routinely for the study of respiratory control in isolated mitochondria. The p(O2) range of respiratory control by oxygen overlaps with cellular oxygen profiles, indicating the significance of p(O2) in actual metabolic regulation. (2) A methodologically detailed discussion of high-resolution respirometry is necessary for the controversial topic of respiratory control by oxygen, since the risk of methodological artefact is closely connected with far-reaching theoretical implications. Instrumental and analytical errors may mask effects of energetic state and partially explain the divergent views on the regulatory role of intracellular p(O2). Oxygen pressure for half-maximum respiration, p(50), in isolated mitochondria at state 4 was 0.025 kPa (0.2 Torr; 0.3 mu M O-2), whereas p(50) in endothelial cells was 0.06-0.08 kPa (0.5 Torr). (3) A model derived from the thermodynamics of irreversible processes was developed which quantitatively accounts for near-hyperbolic flux/p(O2) relations in isolated mitochondria. The apparent p(50) is a function of redox potential and protonmotive force. The protonmotive force collapses after uncoupling and consequently causes a decrease in p(50). Whereas it is becoming accepted that flux control is shared by several enzymes, insufficient attention is paid to the notion of complementary kinetic and thermodynamic flux control mechanisms.