Ca2+ activation of heart mitochondrial oxidative phosphorylation: Role of the F0/F1-ATPase

Paul R. Territo, Vamsi K. Mootha, Stephanie A. French, Robert S. Balaban

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275 Scopus citations


Ca2+ has been postulated as a cytosolic second messenger in the regulation of cardiac oxidative phosphorylation. This hypothesis draws support from the well-known effects of Ca2+ on muscle activity, which is stimulated in parallel with the Ca2+-sensitive dehydrogenases (CaDH). The effects of Ca2+ on oxidative phosphorylation were further investigated in isolated porcine heart mitochondria at the level of metabolic driving force (NADH or Δψ) and ATP production rates (flow). The resulting force-flow (F- F) relationships permitted the analysis of Ca2+ effects on several putative control points within oxidative phosphorylation, simultaneously. The F-F relationships resulting from additions of carbon substrates alone provided a model of pure CaDH activation. Comparing this curve with variable Ca2+ concentration ([Ca2+]) effects revealed an approximate twofold higher ATP production rate than could be explained by a simple increase in NADH or Δψ via CaDH activation. The half-maximal effect of Ca2+ at state 3 was 157 nM and was completely inhibited by ruthenium red (1 μM), indicating matrix dependence of the Ca2+ effect. Arsenate was used as a probe to differentiate between F0/F1-ATPase and adenylate translocase activity by a futile recycling of ADP-arsenate within the matrix, catalyzed by the F0/F1-ATPase. Ca2+ increased the ADP arsenylation rate more than twofold, suggesting a direct effect on the F0/F1-ATPase. These results suggest that Ca2+ activates cardiac aerobic respiration at the level of both the CaDH and F0/F1-ATPase. This type of parallel control of both intermediary metabolism and ATP synthesis may provide a mechanism of altering ATP production rates with minimal changes in the high-energy intermediates as observed in vivo.

Original languageEnglish (US)
Pages (from-to)C423-C435
JournalAmerican Journal of Physiology - Cell Physiology
Issue number2 47-2
StatePublished - 2000


  • ATP synthesis
  • Dehydrogenase
  • Force-flow analysis
  • Metabolism

ASJC Scopus subject areas

  • Physiology
  • Cell Biology

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