Dynamic adaptation of cardiac oxidative phosphorylation is not mediated by simple feedback control

The classic idea about regulation of cardiac oxidative phosphorylation (OxPhos) was that breakdown products of ATP (ADP and P(i)) diffuse freely to the mitochondria to stimulate OxPhos. On the basis of this metabolic feedback control system, the response time of OxPhos (t(mito)) is predicted to be inversely proportional to the mitochondrial aerobic capacity (MAC). We determined t(mito) during steps in heart rate in isolated perfused rabbit hearts (n = 16) before and after reducing MAC with nonsaturating doses of oligomycin. The reduction of MAC was quantified in mitochondria isolated from each perfused heart, dividing oligomycin-sensitive, ADP-stimulated state 3 respiration by oligomycin-insensitive uncoupled respiration. The t(mito) to heart rate steps from 60 to 70 and 80 beats/min was 5. 6 +/- 0.6 and 7.2 +/- 0.8 s (means +/- SE) and increased an estimated 34 and 40% for a 50% decrease in MAC (P < 0.05), respectively, which is much less than the 100% predicted by the feedback hypothesis. For steps to 100 or 120 beats/min, t(mito) was 8.3 +/- 0.5 and 11.2 +/- 0.6 s and was not reduced with decreases in MAC (P > 0.05). We conclude that immediate feedback control by quickly diffusing ADP and P(i) cannot explain the dynamic regulation of cardiac OxPhos. Because calcium entry into the mitochondria also cannot explain the first fast phase of OxPhos activation, we propose that delay of the energy-related signal in the cytoplasm dominates the response time of OxPhos.