Doxorubicin-induced mitochondrial dysfunction is secondary to nuclear p53 activation in H9c2 cardiomyoblasts

Doxorubicin (DOX) is a widely prescribed chemotherapeutic. The hypothesis for the present study is that DOX-induced myocyte apoptosis involves mitochondrial dysfunction that is a consequence of nuclear DOX effects. H9c2 myoblasts were incubated with 0, 0.5 and 1 mu M DOX and nuclear and mitochondrial alterations were determined. Doxorubicin accumulation in the nucleus was detected after 3 h treatment, followed by an increase in p53 and a decrease in mitochondrial membrane potential. Apoptotic markers, such as caspase activation and chromatin condensation were detected after 24 h of DOX treatment. Bax and p53 translocation to mitochondria as well as the formation of Bax clusters in the cytosol were observed. Importantly, pifithrin-alpha, a p53 inhibitor, protected against DOX-induced mitochondrial depolarization, caspase activation and cell death. Mitochondrial dysfunction in H9c2 myoblasts treated with DOX is a consequence of nuclear p53 activation rather than a direct effect of the drug on mitochondria.