Role of Ca2+-independent phospholipase A2γ in Ca2+-induced mitochondrial permeability transition

Gilbert R. Kinsey, Jane McHowat, Kennerly S. Patrick, Rick G. Schnellmann

Research output: Contribution to journalArticlepeer-review

46 Scopus citations

Abstract

Our laboratory previously demonstrated Ca2+-independent phospholipase A2γ (iPLA2γ) 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 iPLA 2γ 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 iPLA 2γ, 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 iPLA2γ activity restored MPT. We also determined that RCM iPLA2γ displays higher activity against plasmenylcholine with AA in the sn-2 position than oleic acid. Ca2+ exposure significantly increased RCM iPLA 2γ activity; however, the Ca2+-induced activation of iPLA2γ 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 iPLA2γ-catalyzed AA liberation.

Original languageEnglish (US)
Pages (from-to)707-715
Number of pages9
JournalJournal of Pharmacology and Experimental Therapeutics
Volume321
Issue number2
DOIs
StatePublished - May 2007
Externally publishedYes

ASJC Scopus subject areas

  • Molecular Medicine
  • Pharmacology

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