A role for the mitochondrial Na(+)-Ca2+ exchanger in the regulation of oxidative phosphorylation in isolated heart mitochondria

Abstract

The role of the Na(+)-Ca2+ exchanger of heart mitochondria in cellular functioning is not yet clear. The objectives of this study were to investigate the effects of stimulation and inhibition of the Na(+)-Ca2+ exchanger on the matrix free Ca2+ concentration in isolated heart mitochondria and to determine the consequences of these changes on the rate of NADH production via Krebs cycle turnover and the oxidative phosphorylation rate (OPR) supported by alpha-ketoglutarate dehydrogenase, a Ca(2+)-regulated matrix enzyme. Activation of Na(+)-Ca2+ exchange by increasing extramitochondrial Na+ concentration was found to decrease the matrix free [Ca2+] in a concentration-dependent manner. Inhibitors of mitochondrial Na(+)-Ca2+ exchange activity inhibited the decrease in matrix free [Ca2+] mediated by Na+. Increasing concentrations of Na+ were also found to inhibit both the rate of NADH production and OPR. Inhibitors of mitochondrial Na(+)-Ca2+ exchange also blocked the effects of Na+ on the rate of NADH production and OPR in a similar concentration range. The results indicate that alterations in matrix free [Ca2+] induced by changes in mitochondrial Na(+)-Ca2+ exchange activity are translated into changes in the rate of NADH production and the overall rate of oxidative phosphorylation.