Publications

• Group VIA phospholipase A2 mitigates palmitate-induced beta-cell mitochondrial injury and apoptosis.

  Song H., Wohltmann M., Tan M., Ladenson J.H., Turk J.

  Palmitate (C16:0) induces apoptosis of insulin-secreting β-cells by processes that involve generation of reactive oxygen species, and chronically elevated blood long chain free fatty acid levels are thought to contribute to β-cell lipotoxicity and the development of diabetes mellitus. Group VIA ph ... >> More

  Palmitate (C16:0) induces apoptosis of insulin-secreting β-cells by processes that involve generation of reactive oxygen species, and chronically elevated blood long chain free fatty acid levels are thought to contribute to β-cell lipotoxicity and the development of diabetes mellitus. Group VIA phospholipase A2 (iPLA2β) affects β-cell sensitivity to apoptosis, and here we examined iPLA2β effects on events that occur in β-cells incubated with C16:0. Such events in INS-1 insulinoma cells were found to include activation of caspase-3, expression of stress response genes (C/EBP homologous protein and activating transcription factor 4), accumulation of ceramide, loss of mitochondrial membrane potential, and apoptosis. All of these responses were blunted in INS-1 cells that overexpress iPLA2β, which has been proposed to facilitate repair of oxidized mitochondrial phospholipids, e.g. cardiolipin (CL), by excising oxidized polyunsaturated fatty acid residues, e.g. linoleate (C18:2), to yield lysophospholipids, e.g. monolysocardiolipin (MLCL), that can be reacylated to regenerate the native phospholipid structures. Here the MLCL content of mouse pancreatic islets was found to rise with increasing iPLA2β expression, and recombinant iPLA2β hydrolyzed CL to MLCL and released oxygenated C18:2 residues from oxidized CL in preference to native C18:2. C16:0 induced accumulation of oxidized CL species and of the oxidized phospholipid (C18:0/hydroxyeicosatetraenoic acid)-glycerophosphoethanolamine, and these effects were blunted in INS-1 cells that overexpress iPLA2β, consistent with iPLA2β-mediated removal of oxidized phospholipids. C16:0 also induced iPLA2β association with INS-1 cell mitochondria, consistent with a role in mitochondrial repair. These findings indicate that iPLA2β confers significant protection of β-cells against C16:0-induced injury. << Less

  J. Biol. Chem. 289:14194-14210(2014) [PubMed] [EuropePMC]

  This publication is cited by 1 other entry.

• The phospholipase iPLA2gamma is a major mediator releasing oxidized aliphatic chains from cardiolipin, integrating mitochondrial bioenergetics and signaling.

  Liu G.Y., Moon S.H., Jenkins C.M., Li M., Sims H.F., Guan S., Gross R.W.

  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 A₂γ (iPLA₂γ)-selective inhibitor (R)-BEL suggested t ... >> More

  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 A₂γ (iPLA₂γ)-selective inhibitor (R)-BEL suggested that iPLA₂γ 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 iPLA₂γ 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 iPLA₂γ, germ-line iPLA₂γ^-/- mice, cardiac myocyte-specific iPLA₂γ 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 iPLA₂γ is the major enzyme responsible for the release of oxidized aliphatic chains from CL. Our results also indicated that iPLA₂γ selectively hydrolyzes 9-hydroxy-octadecenoic acid in comparison to 13-hydroxy-octadecenoic acid from oxidized CLs. Moreover, oxidative stress (ADP, NADPH, and Fe³⁺) resulted in the robust production of oxidized CLs in intact mitochondria from iPLA₂γ^-/- 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 iPLA₂γ-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 iPLA₂γ in lipid second-messenger production and mitochondrial bioenergetics during oxidative stress. << Less

  J. Biol. Chem. 292:10672-10684(2017) [PubMed] [EuropePMC]

  This publication is cited by 2 other entries.