Reperfusion-induced translocation of δPKC to cardiac mitochondria prevents pyruvate dehydrogenase reactivation

Eric N. Churchill, Christopher L. Murriel, Che Hong Chen, Daria Mochly-Rosen, Luke I. Szweda

Research output: Contribution to journalArticle

104 Scopus citations

Abstract

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 δ-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 δPKC activator H 2O 2 during normoxic perfusion, to mimic one aspect of cardiac reperfusion, resulted in loss in PDH activity that was largely attributable to translocation of δPKC to the mitochondria. Evidence indicates that reperfusion-induced translocation of δPKC is associated with phosphorylation of the αE1 subunit of PDH. A potential mechanism is provided by in vitro data demonstrating that δPKC 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 δPKC to the mitochondria during reperfusion likely results in activation of PDK2 and phosphorylation-dependent inhibition of PDH.

Original languageEnglish (US)
Pages (from-to)78-85
Number of pages8
JournalCirculation Research
Volume97
Issue number1
DOIs
Publication statusPublished - Jul 8 2005

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Keywords

  • δPKC
  • Free radicals
  • Ischemia/reperfusion
  • Mitochondria
  • Pyruvate dehydrogenase
  • Pyruvate dehydrogenase kinase

ASJC Scopus subject areas

  • Physiology
  • Cardiology and Cardiovascular Medicine

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