The phospholipase iPLA 2 γ is a major mediator releasing oxidized aliphatic chains from cardiolipin, integrating mitochondrial bioenergetics and signaling.

Autor: Liu GY; From the Department of Chemistry, Washington University, Saint Louis, Missouri 63130 and., Moon SH; Division of Bioorganic Chemistry and Molecular Pharmacology, Department of Medicine., Jenkins CM; Division of Bioorganic Chemistry and Molecular Pharmacology, Department of Medicine., Li M; Division of Bioorganic Chemistry and Molecular Pharmacology, Department of Medicine., Sims HF; Division of Bioorganic Chemistry and Molecular Pharmacology, Department of Medicine., Guan S; Division of Bioorganic Chemistry and Molecular Pharmacology, Department of Medicine., Gross RW; From the Department of Chemistry, Washington University, Saint Louis, Missouri 63130 and rgross@wustl.edu.; Division of Bioorganic Chemistry and Molecular Pharmacology, Department of Medicine.; Department of Developmental Biology, and.; Center for Cardiovascular Research, Department of Medicine, Washington University School of Medicine, Saint Louis, Missouri 63110.
Jazyk: angličtina
Zdroj: The Journal of biological chemistry [J Biol Chem] 2017 Jun 23; Vol. 292 (25), pp. 10672-10684. Date of Electronic Publication: 2017 Apr 25.
DOI: 10.1074/jbc.M117.783068
Abstrakt: Cardiolipin (CL) is a dimeric phospholipid with critical roles in mitochondrial bioenergetics and signaling. Recently, inhibition of the release of oxidized fatty acyl chains from CL by the calcium-independent phospholipase A 2 γ (iPLA 2 γ)-selective inhibitor (R)-BEL suggested that iPLA 2 γ is responsible for the hydrolysis of oxidized CL and subsequent signaling mediated by the released oxidized fatty acids. However, chemical inhibition by BEL is subject to off-target pharmacologic effects. Accordingly, to unambiguously determine the role of iPLA 2 γ in the hydrolysis of oxidized CL, we compared alterations in oxidized CLs and the release of oxidized aliphatic chains from CL in experiments with purified recombinant iPLA 2 γ, germ-line iPLA 2 γ -/- mice, cardiac myocyte-specific iPLA 2 γ transgenic mice, and wild-type mice. Using charge-switch high mass accuracy LC-MS/MS with selected reaction monitoring and product ion accurate masses, we demonstrated that iPLA 2 γ is the major enzyme responsible for the release of oxidized aliphatic chains from CL. Our results also indicated that iPLA 2 γ selectively hydrolyzes 9-hydroxy-octadecenoic acid in comparison to 13-hydroxy-octadecenoic acid from oxidized CLs. Moreover, oxidative stress (ADP, NADPH, and Fe 3+ ) resulted in the robust production of oxidized CLs in intact mitochondria from iPLA 2 γ -/- mice. In sharp contrast, oxidized CLs were readily hydrolyzed in mitochondria from wild-type mice during oxidative stress. Finally, we demonstrated that CL activates the iPLA 2 γ-mediated hydrolysis of arachidonic acid from phosphatidylcholine, thereby integrating the production of lipid messengers from different lipid classes in mitochondria. Collectively, these results demonstrate the integrated roles of CL and iPLA 2 γ in lipid second-messenger production and mitochondrial bioenergetics during oxidative stress.
(© 2017 by The American Society for Biochemistry and Molecular Biology, Inc.)
Databáze: MEDLINE
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