Translocation of δPKC to mitochondria during cardiac reperfusion enhances superoxide anion production and induces loss in mitochondrial function

Activation of the δ-isoform of protein kinase C (δPKC) by certain conditions of oxidative stress results in translocation of the kinase to the mitochondria leading to release of cytochrome c and the induction of apoptosis. In the current study, the effects of myocardial reperfusion-induced δPKC translocation on mitochondrial function were assessed. Mitochondria isolated from hearts that had undergone ischemia (30 min) followed by reperfusion (15 min) exhibited a significant increase in the rate of superoxide anion (O2−) generation. This was associated with the translocation of δPKC to the mitochondria within the first 5 min of reperfusion. δPKC translocation occurred exclusively during reperfusion and could be mimicked by infusion of intact hearts with H2O2 suggesting redox-dependent activation during reperfusion. Infusion of a peptide inhibitor (δV1-1) specific to the δ-isoform of PKC significantly reduced reperfusion-induced increases in mitochondrial O2− generation. Finally, the decline in mitochondrial respiratory activity evident upon prolonged reperfusion (120 min) was completely prevented by inhibition of δPKC translocation. Thus, δPKC represents a cytosolic redox-sensitive molecule that plays an important role in amplification of O2− production and subsequent declines in mitochondrial function during reperfusion.