title: Calcium-independent phospholipase A2 localizes in and protects mitochondria during apoptotic induction by staurosporine.
abstract: 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.
authors.affiliation: Division of Experimental Diabetes and Aging, Department of Geriatrics and Adult Development, Mount Sinai School of Medicine, New York, New York 10029.
authors.forename: Konstantin
authors.initials: K
authors.lastname: Seleznev
authors.affiliation: Division of Experimental Diabetes and Aging, Department of Geriatrics and Adult Development, Mount Sinai School of Medicine, New York, New York 10029.
authors.forename: Chunying
authors.initials: C
authors.lastname: Zhao
authors.affiliation: Division of Experimental Diabetes and Aging, Department of Geriatrics and Adult Development, Mount Sinai School of Medicine, New York, New York 10029.
authors.forename: Xu Hannah
authors.initials: XH
authors.lastname: Zhang
authors.affiliation: Division of Experimental Diabetes and Aging, Department of Geriatrics and Adult Development, Mount Sinai School of Medicine, New York, New York 10029.
authors.forename: Keying
authors.initials: K
authors.lastname: Song
authors.affiliation: Division of Experimental Diabetes and Aging, Department of Geriatrics and Adult Development, Mount Sinai School of Medicine, New York, New York 10029. Electronic address: zhongmin.ma@mssm.edu.
authors.forename: Zhongmin Alex
authors.initials: ZA
authors.lastname: Ma
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D020169:Caspases / Q000378:metabolism; D002460:Cell Line; D054522:Group VI Phospholipases A2; D007425:Intracellular Membranes; D007700:Kinetics; D008564:Membrane Potentials; D008928:Mitochondria / Q000378:metabolism*; D010741:Phospholipases A / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D054467:Phospholipases A2; D017382:Reactive Oxygen Species / Q000378:metabolism; D019311:Staurosporine / Q000494:pharmacology*; D013481:Superoxides; D014158:Transcription, Genetic / Q000187:drug effects
chemical_list: D017382:Reactive Oxygen Species; D013481:Superoxides; D010741:Phospholipases A; D054522:Group VI Phospholipases A2; D054467:Phospholipases A2; D020169:Caspases; D019311:Staurosporine