Genetic ablation of calcium-independent phospholipase A2γ leads to alterations in mitochondrial lipid metabolism and function resulting in a deficient mitochondrial bioenergetic phenotype

David J. Mancuso, Harold F. Sims, Xianlin Han, Christopher M. Jenkins, Ping Guan Shao, Kui Yang, Ho Moon Sung, Terri Pietka, Nada A. Abumrad, Paul H. Schlesinger, Richard W. Gross

Research output: Contribution to journalArticle

108 Scopus citations

Abstract

Previously, we identified a novel calcium-independent phospholipase, designated calcium-independent phospholipase A2 γ (iPLA 2γ), which possesses dual mitochondrial and peroxisomal subcellular localization signals. To identify the roles of iPLA 2γ in cellular bioenergetics, we generated mice null for the iPLA2γ gene by eliminating the active site of the enzyme through homologous recombination. Mice null for iPLA2γ display multiple bioenergetic dysfunctional phenotypes, including 1) growth retardation, 2) cold intolerance, 3) reduced exercise endurance, 4) greatly increased mortality from cardiac stress after transverse aortic constriction, 5) abnormal mitochondrial function with a 65% decrease in ascorbate-induced Complex IV-mediated oxygen consumption, and 6) a reduction in myocardial cardiolipin content accompanied by an altered cardiolipin molecular species composition. We conclude that iPLA2γ is essential for maintaining efficient bioenergetic mitochondrial function through tailoring mitochondrial membrane lipid metabolism and composition.

Original languageEnglish (US)
Pages (from-to)34611-34622
Number of pages12
JournalJournal of Biological Chemistry
Volume282
Issue number48
DOIs
StatePublished - Nov 30 2007
Externally publishedYes

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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    Mancuso, D. J., Sims, H. F., Han, X., Jenkins, C. M., Shao, P. G., Yang, K., Sung, H. M., Pietka, T., Abumrad, N. A., Schlesinger, P. H., & Gross, R. W. (2007). Genetic ablation of calcium-independent phospholipase A2γ leads to alterations in mitochondrial lipid metabolism and function resulting in a deficient mitochondrial bioenergetic phenotype. Journal of Biological Chemistry, 282(48), 34611-34622. https://doi.org/10.1074/jbc.M707795200