Selective activation of the sodium-independent, cyclosporine a-sensitive calcium pore of cardiac mitochondria by doxorubicin

Various potentially cytopathic actions of doxorubicin have been implicated in the development of cardiotoxicity. However, inhibition of mitochondrial respiration and disruption of calcium homeostasis are emerging as possible primary determinants of toxicity. The objective of this investigation was to identify the specific ion channel by which doxorubicin interferes with calcium homeostasis in isolated rat heart mitochondria. Calcium accumulation by tightly coupled mitochondria was determined spectrophotometrically using arsenazo III and membrane potential was monitored fluorometrically with rhodamine 123. Incubation of cardiac mitochondria with doxorubicin caused a decrease in net accumulation and a delayed spontaneous release of calcium. There was no discernable dissipation of membrane potential and no detectable effect of the drug on the electrophoretic uniport. Diltiazem had no effect while cyclosporin A completely inhibited doxorubicin-induced calcium release. Addition of cyclosporin A prior to calcium prevented the doxorubicin-induced inhibition of calcium accumulation and the release of calcium from cardiac mitochondria. These data suggest that doxorubicin has a specific action on the mitochondrial ADP/ATP antiport, independent of the electrophoretic uniport and the sodium-dependent antiport, which may initiate calcium cycling and the consequential inhibition of oxidative phosphorylation.