Studies of Physiological Control of ATP Synthesis

Studies of the control of cardiac respiration using isolated heart mitochondria and submitochondrial particles are reviewed and compared with studies of cardiac respiration in perfused hearts and in intact organisms. The studies of respiratory control in isolated mitochondria indicate that the rate of ATP synthesis is controlled by the substrates of the reaction, phosphate and ADP, and by the electrochemical potential gradient of protons across the mitochondrial inner membrane. The controversy about whether the ATP synthase itself or the adenine nucleotide translocase provides kinetic limitation to flux is discussed from the point of view that the more important kinetic control is provided by the synthase. When rates of ATP synthesis are varied in intact organs other than the adult mammalian heart, NMR measurements suggest that free ADPalso controls respiration and ATP synthesis in vivo . However, in the adult heart in vivo there appears to be an additional control mechanism which permits ATP synthesis to vary over a 5- to 6-fold range in the absence of appropriate increases in substrate level or increases in the electrochemical potential gradient of protons, a value recently measured in working hearts. Possible mechanisms are discussed in light of reports of allosteric control of the ATP synthase gathered using submitochondrial particles.