Protection of pancreatic beta-cells by group VIA phospholipase A(2)-mediated repair of mitochondrial membrane peroxidation.

Abstract

Mitochondrial production of reactive oxygen species and oxidation of cardiolipin are key events in initiating apoptosis. We reported that group VIA Ca(2+)-independent phospholipase A(2) (iPLA(2)beta) localizes in and protects beta-cell mitochondria from oxidative damage during staurosporine-induced apoptosis. Here, we used iPLA(2)beta-null (iPLA(2)beta(-/-)) mice to investigate the role of iPLA(2)beta in the repair of mitochondrial membranes. We show that islets isolated from iPLA(2)beta(-/-) 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 iPLA(2)beta(-/-) mice impairs both the animals' glucose tolerance and glucose-stimulated insulin secretion by their pancreatic islets. Moreover, the iPLA(2)beta 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 iPLA(2)beta(-/-) 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(2)beta. Interestingly, iPLA(2)beta was expressed only at low levels in islet beta-cells from obesity- and diabetes-prone db/db mice. These findings support the hypothesis that iPLA(2)beta 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 iPLA(2)beta expression level in db/db mouse beta-cells may render them vulnerable to injury by reactive oxygen species.

• Authors: Zhengshan Zhao, Xu Zhang, Chunying Zhao, Jinwoo Choi, Jieyi Shi, Keying Song, John Turk, Zhongmin Alex Ma
• Journal: Endocrinology (Endocrinology) Vol. 151 Issue 7 Pg. 3038-48 (Jul 2010) ISSN: 1945-7170 [Electronic] United States
• PMID: 20463052 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Cardiolipins
• Insulin
• Phospholipids
• Palmitic Acid
• Cytochromes c
• Group VI Phospholipases A2
• Caspase 3
• Staurosporine
• Glucose

Topics

• Animals
• Apoptosis
• Blotting, Western
• Cardiolipins (metabolism)
• Caspase 3 (metabolism)
• Cells, Cultured
• Cytochromes c (metabolism)
• Glucose (pharmacology)
• Glucose Tolerance Test
• Group VI Phospholipases A2 (genetics, metabolism)
• Immunohistochemistry
• Insulin (metabolism)
• Insulin-Secreting Cells (drug effects, metabolism)
• Islets of Langerhans (drug effects, metabolism)
• Lipid Peroxidation (drug effects)
• Membrane Potential, Mitochondrial (drug effects)
• Mice
• Mice, Knockout
• Mitochondrial Membranes (drug effects, metabolism)
• Palmitic Acid (pharmacology)
• Phospholipids (metabolism)
• Random Allocation
• Staurosporine (pharmacology)