Genetic ablation of calcium-independent phospholipase A2gamma 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 A(2) gamma (iPLA(2)gamma), which possesses dual mitochondrial and peroxisomal subcellular localization signals. To identify the roles of iPLA(2)gamma in cellular bioenergetics, we generated mice null for the iPLA(2)gamma gene by eliminating the active site of the enzyme through homologous recombination. Mice null for iPLA(2)gamma 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 iPLA(2)gamma is essential for maintaining efficient bioenergetic mitochondrial function through tailoring mitochondrial membrane lipid metabolism and composition.
Mancuso
David J
DJ
Division of Bioorganic Chemistry and Molecular Pharmacology, Department of Medicine, Washington University School of Medicine, St. Louis, Missouri 63110, USA.
Sims
Harold F
HF
Han
Xianlin
X
Jenkins
Christopher M
CM
Guan
Shao Ping
SP
Yang
Kui
K
Moon
Sung Ho
SH
Pietka
Terri
T
Abumrad
Nada A
NA
Schlesinger
Paul H
PH
Gross
Richard W
RW
D000818:Animals; D001011:Aorta / Q000378:metabolism; D002118:Calcium / Q000378:metabolism*; D017931:DNA Primers / Q000737:chemistry; D005260:Female; D005821:Genetic Techniques; D054513:Group IV Phospholipases A2 / Q000235:genetics* / Q000502:physiology*; D050356:Lipid Metabolism; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D008928:Mitochondria / Q000378:metabolism*; D009206:Myocardium / Q000378:metabolism; D010101:Oxygen Consumption; D010641:Phenotype; D011995:Recombination, Genetic
D017931:DNA Primers; D054513:Group IV Phospholipases A2; D002118:Calcium