Ca(2+) activation of heart mitochondrial oxidative phosphorylation: role of the F(0)/F(1)-ATPase

Am J Physiol Cell Physiol. 2000 Feb;278(2):C423-35. doi: 10.1152/ajpcell.2000.278.2.C423.


Ca(2+) 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 Ca(2+) on muscle activity, which is stimulated in parallel with the Ca(2+)-sensitive dehydrogenases (CaDH). The effects of Ca(2+) on oxidative phosphorylation were further investigated in isolated porcine heart mitochondria at the level of metabolic driving force (NADH or Deltapsi) and ATP production rates (flow). The resulting force-flow (F-F) relationships permitted the analysis of Ca(2+) 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 Ca(2+) concentration ([Ca(2+)]) effects revealed an approximate twofold higher ATP production rate than could be explained by a simple increase in NADH or Deltapsi via CaDH activation. The half-maximal effect of Ca(2+ )at state 3 was 157 nM and was completely inhibited by ruthenium red (1 microM), indicating matrix dependence of the Ca(2+) effect. Arsenate was used as a probe to differentiate between F(0)/F(1)-ATPase and adenylate translocase activity by a futile recycling of ADP-arsenate within the matrix, catalyzed by the F(0)/F(1)-ATPase. Ca(2+) increased the ADP arsenylation rate more than twofold, suggesting a direct effect on the F(0)/F(1)-ATPase. These results suggest that Ca(2+) activates cardiac aerobic respiration at the level of both the CaDH and F(0)/F(1)-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.

MeSH terms

  • Adenosine Triphosphate / biosynthesis
  • Animals
  • Arsenates / pharmacology
  • Calcium / metabolism*
  • Calcium / pharmacology
  • Carbonyl Cyanide p-Trifluoromethoxyphenylhydrazone / pharmacology
  • Dose-Response Relationship, Drug
  • Membrane Potentials / drug effects
  • Membrane Potentials / physiology
  • Mitochondria / enzymology*
  • Myocardium / enzymology*
  • NAD / biosynthesis
  • Oxidative Phosphorylation
  • Oxidoreductases / metabolism
  • Oxygen Consumption / drug effects
  • Oxygen Consumption / physiology
  • Proton-Translocating ATPases / metabolism*
  • Regression Analysis
  • Substrate Specificity
  • Swine
  • Uncoupling Agents / pharmacology


  • Arsenates
  • Uncoupling Agents
  • NAD
  • Carbonyl Cyanide p-Trifluoromethoxyphenylhydrazone
  • Adenosine Triphosphate
  • Oxidoreductases
  • Proton-Translocating ATPases
  • Calcium