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J. Biol. Chem., Vol. 281, Issue 31, 22275-22288, August 4, 2006

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Calcium-independent Phospholipase A₂ Localizes in and Protects Mitochondria during Apoptotic Induction by Staurosporine^*

From the Division of Experimental Diabetes and Aging, Department of Geriatrics and Adult Development, Mount Sinai School of Medicine, New York, New York 10029

Mitochondria-mediated production of reactive oxygen species (ROS) plays a key role in apoptosis. Mitochondrial phospholipid cardiolipin molecules are likely the main target of ROS because they are particularly rich in polyunsaturated fatty acids. They are also located in the inner mitochondrial membrane near the ROS-producing sites. Under physiological conditions mitochondria can repair peroxidative damage in part through a remodeling mechanism via the deacylation-reacylation cycle mediated by phospholipase A₂ (PLA₂) and acyl-coenzyme A-dependent monolysocardiolipin acyltransferase. Here we investigate whether group VIA Ca²⁺-independent PLA₂ (iPLA₂) plays a role in the protection of mitochondrial function from damage caused by mitochondrially generated ROS during apoptotic induction by staurosporine (STS). We show that iPLA₂-expressing cells were relatively resistant to STS-induced apoptosis. iPLA₂ localized to mitochondria even before apoptotic induction, and most iPLA₂-associated mitochondria were intact in apoptotic resistant cells. Expression of iPLA₂ in INS-1 cells prevented the loss of mitochondrial membrane potential, attenuated the release of cytochrome c, Smac/DIABLO, and apoptosis inducing factor from mitochondria, and reduced mitochondrial reactive oxygen species production. Inhibition of caspase 8 has little effect on STS-induced apoptosis in INS-1 cells. Finally, we found that STS down-regulated endogenous iPLA₂ transcription in both INS-1 and iPLA₂-expressing INS-1 cells without affecting the expression of group IV Ca²⁺-dependent PLA₂. Together, our data indicate that iPLA₂ is important for the protection of mitochondrial function from oxidative damage during apoptotic induction. Down-regulation of endogenous iPLA₂ by STS may result in the loss of mitochondrial membrane repair functions and lead to mitochondrial failure and apoptosis.

Received for publication, May 5, 2006

^* This work is supported by grants from the NIDDK, National Institutes of Health and the Juvenile Diabetes Research Foundation, International. 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. Tel.: 212-241-5651; Fax: 212-241-7248; E-mail: zhongmin.ma{at}mssm.edu.

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