Translocation of deltaPKC to mitochondria during cardiac reperfusion enhances superoxide anion production and induces loss in mitochondrial function.
Activation of the delta-isoform of protein kinase C (deltaPKC) 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 deltaPKC 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 (O(2)(-)) generation. This was associated with the translocation of deltaPKC to the mitochondria within the first 5 min of reperfusion. deltaPKC translocation occurred exclusively during reperfusion and could be mimicked by infusion of intact hearts with H(2)O(2) suggesting redox-dependent activation during reperfusion. Infusion of a peptide inhibitor (deltaV(1-1)) specific to the delta-isoform of PKC significantly reduced reperfusion-induced increases in mitochondrial O(2)(-) generation. Finally, the decline in mitochondrial respiratory activity evident upon prolonged reperfusion (120min) was completely prevented by inhibition of deltaPKC translocation. Thus, deltaPKC represents a cytosolic redox-sensitive molecule that plays an important role in amplification of O(2)(-) production and subsequent declines in mitochondrial function during reperfusion.
Churchill
Eric N
EN
Department of Physiology and Biophysics, Case Western Reserve University, Cleveland, OH 44106-4907, USA.
Szweda
Luke I
LI
D000818:Animals; D003600:Cytosol / Q000378:metabolism; D004579:Electron Transport; D004791:Enzyme Inhibitors / Q000494:pharmacology; D066298:In Vitro Techniques; D008297:Male; D008929:Mitochondria, Heart / Q000378:metabolism*; D017202:Myocardial Ischemia / Q000378:metabolism; D015425:Myocardial Reperfusion; D015428:Myocardial Reperfusion Injury / Q000378:metabolism / Q000517:prevention & control; D018384:Oxidative Stress; D010455:Peptides / Q000378:metabolism / Q000494:pharmacology; D011493:Protein Kinase C / Q000037:antagonists & inhibitors / Q000378:metabolism*; D051745:Protein Kinase C-delta; D021381:Protein Transport; D051381:Rats; D017207:Rats, Sprague-Dawley; D013481:Superoxides / Q000378:metabolism*
D004791:Enzyme Inhibitors; D010455:Peptides; D013481:Superoxides; C497260:Prkcd protein, rat; D011493:Protein Kinase C; D051745:Protein Kinase C-delta