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J. Biol. Chem., Vol. 282, Issue 48, 34611-34622, November 30, 2007

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Genetic Ablation of Calcium-independent Phospholipase A₂ Leads to Alterations in Mitochondrial Lipid Metabolism and Function Resulting in a Deficient Mitochondrial Bioenergetic Phenotype^*

David J. Mancuso, Harold F. Sims, Xianlin Han, Christopher M. Jenkins, Shao Ping Guan, Kui Yang, Sung Ho Moon, Terri Pietka^¶, Nada A. Abumrad^¶||, Paul H. Schlesinger^||, and Richard W. Gross^**1

From the Divisions of Bioorganic Chemistry and Molecular Pharmacology and ^¶Nutritional Sciences, Departments of Medicine, ^||Cell Biology and Physiology, and ^**Molecular Biology and Pharmacology, Washington University School of Medicine, St. Louis, Missouri 63110 and the Department of Chemistry, Washington University, St. Louis, Missouri 63130

Previously, we identified a novel calcium-independent phospholipase, designated calcium-independent phospholipase A₂ (iPLA₂), which possesses dual mitochondrial and peroxisomal subcellular localization signals. To identify the roles of iPLA₂ in cellular bioenergetics, we generated mice null for the iPLA₂ gene by eliminating the active site of the enzyme through homologous recombination. Mice null for iPLA₂ display multiple bioenergetic dysfunctional phenotypes, including 1) growth retardation, 2) cold intolerance, 3) reduced exercise endurance, 4) greatly increased mortality from cardiac stress after transverse aortic constriction, 5) abnormal mitochondrial function with a 65% decrease in ascorbate-induced Complex IV-mediated oxygen consumption, and 6) a reduction in myocardial cardiolipin content accompanied by an altered cardiolipin molecular species composition. We conclude that iPLA₂ is essential for maintaining efficient bioenergetic mitochondrial function through tailoring mitochondrial membrane lipid metabolism and composition.

Received for publication, September 17, 2007 , and in revised form, October 5, 2007.

^* This research was supported by National Institutes of Health Grant 5PO1HL57278-10 and by Clinical Nutrition Research Unit Grant DK56351. 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: Washington University School of Medicine, Division of Bioorganic Chemistry and Molecular Pharmacology, 660 S. Euclid Ave., Campus Box 8020, St. Louis, MO 63110. Tel.: 314-362-2690; Fax: 314-362-1402; E-mail: rgross{at}wustl.edu.

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