Published online before print June 16, 2005, doi: 10.1161/01.RES.0000173896.32522.6e
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© 2005 American Heart Association, Inc.
Integrative Physiology |
Reperfusion-Induced Translocation of 
PKC to Cardiac Mitochondria Prevents Pyruvate Dehydrogenase Reactivation
From the Department of Physiology and Biophysics (E.N.C., L.I.S.), Case Western Reserve University, Cleveland, Ohio; and the Department of Molecular Pharmacology (C.L.M., C.-H.C., D.M.-R.), Stanford University School of Medicine, Calif.
Correspondence to Luke I. Szweda, Oklahoma Medical Research Foundation, 825 NE 13th St, Oklahoma City, OK 73104. E-mail Luke-Szweda{at}omrf.ouhsc.edu
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 
-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 PKC 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 PKC to the mitochondria. Evidence indicates that reperfusion-induced translocation of PKC is associated with phosphorylation of the 
E1 subunit of PDH. A potential mechanism is provided by in vitro data demonstrating that PKC 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 PKC to the mitochondria during reperfusion likely results in activation of PDK2 and phosphorylation-dependent inhibition of PDH.
Key Words: pyruvate dehydrogenase • PKC • pyruvate dehydrogenase kinase • free radicals • mitochondria • ischemia/reperfusion
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