Protection of pancreatic β-cells by group VIA phospholipase A 2-mediated repair of mitochondrial membrane peroxidation

Zhengshan Zhao, Xu Zhang, Chunying Zhao, Jinwoo Choi, Jieyi Shi, Keying Song, John Turk, Zhongmin Alex Ma

Research output: Contribution to journalArticlepeer-review

61 Scopus citations


Mitochondrial production of reactive oxygen species and oxidation of cardiolipin are key events in initiating apoptosis. We reported that group VIA Ca2+-independent phospholipase A2 (iPLA2 β) localizes in and protects β-cell mitochondria from oxidative damage during staurosporine-induced apoptosis. Here, we used iPLA2β-null (iPLA2β-/-) mice to investigate the role of iPLA 2βin the repair of mitochondrial membranes. We show that islets isolated from iPLA2β-/- mice are more sensitive to staurosporine-induced apoptosis than those from wild-type littermates and that 2 wk of daily ip administration of staurosporine to iPLA2β -/- mice impairs both the animals' glucose tolerance and glucose-stimulated insulin secretion by their pancreatic islets. Moreover, the iPLA2β inhibitor bromoenol lactone caused mitochondrial membrane peroxidation and cytochrome c release, and these effects were reversed by N-acetyl cysteine. The mitochondrial antioxidant N-t-butyl hydroxylamine blocked staurosporine-induced cytochrome c release and caspase-3 activation in iPLA2β-/- islets. Furthermore, the collapse of mitochondrial membrane potential in INS-1 insulinoma cells caused by high glucose and fatty acid levels was attenuated by overexpressing iPLA 2β. Interestingly, iPLA2β was expressed only at low levels in islet β-cells from obesity- and diabetes-prone db/db mice. These findings support the hypothesis that iPLA2β is important in repairing oxidized mitochondrial membrane components (e.g. cardiolipin) and that this prevents cytochrome c release in response to stimuli that otherwise induce apoptosis. The low iPLA2β expression level in db/db mouse β-cells may render them vulnerable to injury by reactive oxygen species.

Original languageEnglish
Pages (from-to)3038-3048
Number of pages11
Issue number7
StatePublished - Jul 2010


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