Reperfusion-induced translocation of deltaPKC to cardiac mitochondria prevents pyruvate dehydrogenase reactivation.
Cardiac ischemia and reperfusion are associated with loss in the activity of the mitochondrial enzyme pyruvate dehydrogenase (PDH). Pharmacological stimulation of PDH activity improves recovery in contractile function during reperfusion. Signaling mechanisms that control inhibition and reactivation of PDH during reperfusion were therefore investigated. Using an isolated rat heart model, we observed ischemia-induced PDH inhibition with only partial recovery evident on reperfusion. Translocation of the redox-sensitive delta-isoform of protein kinase C (PKC) to the mitochondria occurred during reperfusion. Inhibition of this process resulted in full recovery of PDH activity. Infusion of the deltaPKC activator H2O2 during normoxic perfusion, to mimic one aspect of cardiac reperfusion, resulted in loss in PDH activity that was largely attributable to translocation of deltaPKC to the mitochondria. Evidence indicates that reperfusion-induced translocation of deltaPKC is associated with phosphorylation of the alphaE1 subunit of PDH. A potential mechanism is provided by in vitro data demonstrating that deltaPKC specifically interacts with and phosphorylates pyruvate dehydrogenase kinase (PDK)2. Importantly, this results in activation of PDK2, an enzyme capable of phosphorylating and inhibiting PDH. Thus, translocation of deltaPKC to the mitochondria during reperfusion likely results in activation of PDK2 and phosphorylation-dependent inhibition of PDH.
Churchill
Eric N
EN
Department of Physiology and Biophysics, Case Western Reserve University, Cleveland, Ohio, USA.
Murriel
Christopher L
CL
Chen
Che-Hong
CH
Mochly-Rosen
Daria
D
Szweda
Luke I
LI
D000818:Animals; D004789:Enzyme Activation; D006861:Hydrogen Peroxide / Q000494:pharmacology; D008297:Male; D008929:Mitochondria, Heart / Q000201:enzymology*; D015425:Myocardial Reperfusion; D010766:Phosphorylation; D011493:Protein Kinase C / Q000378:metabolism*; D051745:Protein Kinase C-delta; D011494:Protein Kinases / Q000378:metabolism*; D017346:Protein Serine-Threonine Kinases; D021381:Protein Transport; D000081382:Pyruvate Dehydrogenase Acetyl-Transferring Kinase; D011768:Pyruvate Dehydrogenase Complex / Q000037:antagonists & inhibitors*; D051381:Rats; D017207:Rats, Sprague-Dawley
C000631436:Pdk2 protein, rat; D000081382:Pyruvate Dehydrogenase Acetyl-Transferring Kinase; D011768:Pyruvate Dehydrogenase Complex; D006861:Hydrogen Peroxide; D011494:Protein Kinases; C497260:Prkcd protein, rat; D017346:Protein Serine-Threonine Kinases; D011493:Protein Kinase C; D051745:Protein Kinase C-delta