Identification of calcium-independent phospholipase A2γ in mitochondria and its role in mitochondrial oxidative stress

Gilbert R. Kinsey, Jane McHowat, Caroline S. Beckett, Rick G. Schnellmann

Research output: Contribution to journalArticlepeer-review

46 Scopus citations

Abstract

Oxidant-induced lipid peroxidation and cell death mediate pathologies associated with ischemia-reperfusion and inflammation. Our previous work in rabbit renal proximal tubular cells (RPTC) demonstrated that inhibition of Ca2+-independent phospholipase A2 (iPLA2) potentiates oxidant-induced lipid peroxidation and necrosis, implicating iPLA2 in phospholipid repair. This study was conducted to identify a RPTC mitochondrial PLA2 and determine the role of PLA2 in oxidant-induced mitochondrial dysfunction. iPLA2 activity was detected in Percoll-purified rabbit renal cortex mitochondria (RCM) and in isolated mitochondrial inner membrane fractions from rabbit and human RCM. Immunoblot analysis and inhibitor sensitivity profiles revealed that iPLA 2γ is the RCM iPLA2 activity. RCM iPLA2 activity was enhanced in the presence of ATP and was blocked by the PKCε V1-2 inhibitor. Oxidant-induced mitochondrial lipid peroxidation and swelling were accelerated by pretreatment with R-BEL, but not S-BEL. Furthermore, oxidant treatment of isolated RCM resulted in decreased iPLA2γ activity. These results reveal that RCM iPLA2 is iPLA 2γ, RCM iPLA2γ is regulated by phosphorylation by PKCε, iPLA2γ protects RCM from oxidant-induced lipid peroxidation and dysfunction, and that a strategy to preserve or enhance iPLA2γ activity may be of therapeutic benefit.

Original languageEnglish (US)
Pages (from-to)F853-F860
JournalAmerican Journal of Physiology - Renal Physiology
Volume292
Issue number2
DOIs
StatePublished - Feb 2007
Externally publishedYes

Keywords

  • Group VIB PLA
  • Lipid peroxidation

ASJC Scopus subject areas

  • Physiology
  • Urology

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