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TOXICOLOGY

Role of Ca²⁺-Independent Phospholipase A₂ in Ca²⁺-Induced Mitochondrial Permeability Transition

Department of Pharmaceutical Sciences, Medical University of South Carolina, Charleston, South Carolina, (G.R.K., K.S.P., R.G.S.); and Department of Pathology, St. Louis University, St. Louis, Missouri (J.M.)

Our laboratory previously demonstrated Ca²⁺-independent phospholipase A₂ (iPLA₂) is localized to mitochondria and that iPLA₂ inhibition blocks cisplatin-induced caspase-mediated apoptosis. Whereas the mitochondrial permeability transition (MPT) is a key control point for apoptosis, the role of mitochondrial iPLA₂ in MPT has not been established. In the present study, we addressed this issue. Ca²⁺-induced renal cortex mitochondrial (RCM) swelling was blocked by the MPT inhibitor cyclosporine A. The R-isomer of bromoenol lactone (R-BEL), which enantiospecifically inhibits iPLA₂, inhibited Ca²⁺-induced RCM MPT, whereas S-BEL (negative control) had no effect. Ca²⁺ treatment resulted in a significant increase in free arachidonic acid (AA) (>50 µM) in the RCM suspension that was blocked by pretreatment with BEL. No increases in free myristic, palmitic, stearic, oleic, linoleic, or docosahexaenoic acid were detected after Ca²⁺ treatment. The addition of AA (18 µM) to Ca²⁺-treated RCM with inhibited iPLA₂ activity restored MPT. We also determined that RCM iPLA₂ displays higher activity against plasmenylcholine with AA in the sn-2 position than oleic acid. Ca²⁺ exposure significantly increased RCM iPLA₂ activity; however, the Ca²⁺-induced activation of iPLA₂ was not the result of mitochondrial membrane potential dissipation, opening of the MPT pore, or mitochondrial swelling. Taken together these findings provide strong evidence that Ca²⁺-induced RCM MPT is mediated by iPLA₂-catalyzed AA liberation.

Address correspondence to: Dr. Rick G. Schnellmann, Medical University of South Carolina, Department of Pharmaceutical Sciences, 280 Calhoun St., Charleston, SC 29425. E-mail: schnell{at}musc.edu

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