Dynamic adaptation of cardiac oxidative phosphorylation is not mediated bysimple feedback control

The classic idea about regulation of cardiac oxidative phosphorylation (OxP hos) 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 in versely proportional to the mitochondrial aerobic capacity (MAC). We determ ined t(mito) during steps in heart rate in isolated perfused rabbit hearts (n = 16) before and after reducing MAC with nonsaturating doses of oligomyc in. The reduction of MAC was quantified in mitochondria isolated from each perfused heart, dividing oligomycin-sensitive, ADP-stimulated state 3 respi ration by oligomycin-insensitive uncoupled respiration. The t(mito) to hear t 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. Becau se calcium entry into the mitochondria also cannot explain the first fast p hase of OxPhos activation, we propose that delay of the energy-related sign al in the cytoplasm dominates the response time of OxPhos.