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

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.