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J. Biol. Chem., Vol. 283, Issue 44, 29831-29840, October 31, 2008

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Delta Protein Kinase C Interacts with the d Subunit of the F₁F₀ ATPase in Neonatal Cardiac Myocytes Exposed to Hypoxia or Phorbol Ester

IMPLICATIONS FOR F₁F₀ ATPase REGULATION^*

Tiffany Nguyen, Mourad Ogbi, and John A. Johnson¹

From the Department of Pharmacology and Toxicology, School of Medicine, and the Program in Regenerative Medicine, Institute of Molecular Medicine and Genetics, Medical College of Georgia, Augusta, Georgia 30912-2300

Mitochondrial protein kinase C isozymes have been reported to mediate both cardiac ischemic preconditioning and ischemia/reperfusion injury. In addition, cardiac preconditioning improves the recovery of ATP levels after ischemia/reperfusion injury. We have, therefore, evaluated protein kinase C modulation of the F₁F₀ ATPase in neonatal cardiac myocytes. Exposure of cells to 3 or 100 nM 4β-phorbol 12-myristate-13-acetate induced co-immunoprecipitation of protein kinase C (but not , , or protein kinase C) with the d subunit of the F₁F₀ ATPase. This co-immunoprecipitation correlated with 40 ± 3% and 72 ± 9% inhibitions of oligomycin-sensitive F₁F₀ ATPase activity, respectively. We observed prominent expression of protein kinase C in cardiac myocyte mitochondria, which was enhanced following a 4-h hypoxia exposure. In contrast, hypoxia decreased mitochondrial PKC levels by 85 ± 1%. Following 4 h of hypoxia, F₁F₀ ATPase activity was inhibited by 75 ± 9% and protein kinase C co-immunoprecipitated with the d subunit of F₁F₀ ATPase. In vitro incubation of protein kinase C with F₁F₀ ATPase enhanced F₁F₀ activity in the absence of protein kinase C activators and inhibited it in the presence of activators. Recombinant protein kinase C also inhibited F₁F₀ ATPase activity. Protein kinase C overlay assays revealed protein kinase C binding to the d subunit of F₁F₀ ATPase, which was modulated by diacylglycerol, phosphatidylserine, and cardiolipin. Our results suggest a novel regulation of the F₁F₀ ATPase by the protein kinase C isozyme.

Received for publication, February 29, 2008 , and in revised form, August 6, 2008.

^* This work was supported, in whole or in part, by National Institutes of Health Grant R01HL76805 (to J. A. J.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ To whom correspondence should be addressed: 1459 Laney Walker Blvd., Augusta, GA 30912. Tel.: 706-721-4173; Fax: 706-721-2347; E-mail: jjohnson{at}mail.mcg.edu.

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