Protection of pancreatic beta-cells by group VIA phospholipase A(2)-mediated repair of mitochondrial membrane peroxidation.
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.
Zhao
Zhengshan
Z
Division of Experimental Diabetes and Aging, Department of Geriatrics and Adult Development, One Gustave L. Levy Place, Mount Sinai School of Medicine, New York, NY 10029, USA.
Zhang
Xu
X
Zhao
Chunying
C
Choi
Jinwoo
J
Shi
Jieyi
J
Song
Keying
K
Turk
John
J
Ma
Zhongmin Alex
ZA
D000818:Animals; D017209:Apoptosis; D015153:Blotting, Western; D002308:Cardiolipins / Q000378:metabolism; D053148:Caspase 3 / Q000378:metabolism; D002478:Cells, Cultured; D045304:Cytochromes c / Q000378:metabolism; D005947:Glucose / Q000494:pharmacology; D005951:Glucose Tolerance Test; D054522:Group VI Phospholipases A2 / Q000235:genetics / Q000378:metabolism*; D007150:Immunohistochemistry; D007328:Insulin / Q000378:metabolism; D050417:Insulin-Secreting Cells / Q000187:drug effects / Q000378:metabolism*; D007515:Islets of Langerhans / Q000187:drug effects / Q000378:metabolism; D015227:Lipid Peroxidation / Q000187:drug effects; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D051379:Mice; D018345:Mice, Knockout; D051336:Mitochondrial Membranes / Q000187:drug effects / Q000378:metabolism*; D019308:Palmitic Acid / Q000494:pharmacology; D010743:Phospholipids / Q000378:metabolism; D011897:Random Allocation; D019311:Staurosporine / Q000494:pharmacology
D002308:Cardiolipins; D007328:Insulin; D010743:Phospholipids; D019308:Palmitic Acid; D045304:Cytochromes c; D054522:Group VI Phospholipases A2; D053148:Caspase 3; D019311:Staurosporine; D005947:Glucose
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