title: 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.affiliation: 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.
authors.forename: Zhengshan
authors.initials: Z
authors.lastname: Zhao
authors.forename: Xu
authors.initials: X
authors.lastname: Zhang
authors.forename: Chunying
authors.initials: C
authors.lastname: Zhao
authors.forename: Jinwoo
authors.initials: J
authors.lastname: Choi
authors.forename: Jieyi
authors.initials: J
authors.lastname: Shi
authors.forename: Keying
authors.initials: K
authors.lastname: Song
authors.forename: John
authors.initials: J
authors.lastname: Turk
authors.forename: Zhongmin Alex
authors.initials: ZA
authors.lastname: Ma
mesh_terms: 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
chemical_list: D002308:Cardiolipins; D007328:Insulin; D010743:Phospholipids; D019308:Palmitic Acid; D045304:Cytochromes c; D054522:Group VI Phospholipases A2; D053148:Caspase 3; D019311:Staurosporine; D005947:Glucose
references.citation: Diabetes. 1983 Nov;32(11):1048-54
references.pmid: 6357903
references.citation: J Cell Sci. 2006 Mar 15;119(Pt 6):1005-15
references.pmid: 16492706
references.citation: Biochim Biophys Acta. 2000 Oct 31;1488(1-2):1-19
references.pmid: 11080672
references.citation: Nat Genet. 2006 Jul;38(7):752-4
references.pmid: 16783378
references.citation: Autoimmunity. 2007 Jun;40(4):267-73
references.pmid: 17516208
references.citation: J Biol Chem. 2003 Jun 20;278(25):22231-6
references.pmid: 12719436
references.citation: J Clin Invest. 2006 Jul;116(7):1802-12
references.pmid: 16823478
references.citation: J Biol Chem. 2004 Sep 10;279(37):38194-200
references.pmid: 15252026
references.citation: J Biol Chem. 2004 Sep 24;279(39):40385-91
references.pmid: 15252038
references.citation: Biochim Biophys Acta. 2009 Oct;1788(10):2048-58
references.pmid: 19539604
references.citation: Nat Chem Biol. 2005 Sep;1(4):223-32
references.pmid: 16408039
references.citation: J Clin Invest. 1978 Feb;61(2):243-50
references.pmid: 340468
references.citation: J Biol Chem. 2006 Aug 4;281(31):22275-22288
references.pmid: 16728389
references.citation: J Biol Chem. 1998 May 29;273(22):13870-7
references.pmid: 9593733
references.citation: Proc Natl Acad Sci U S A. 2009 Feb 17;106(7):2337-41
references.pmid: 19164547
references.citation: Prog Nucleic Acid Res Mol Biol. 2001;67:1-33
references.pmid: 11525380
references.citation: Biochim Biophys Acta. 1986 Dec 5;879(3):399-409
references.pmid: 3535899
references.citation: Biochim Biophys Acta. 2009 Oct;1788(10):2022-31
references.pmid: 19450542
references.citation: Cell. 2003 Jun 13;113(6):717-30
references.pmid: 12809603
references.citation: J Cell Sci. 2007 Dec 1;120(Pt 23):4134-43
references.pmid: 18032786
references.citation: Biochim Biophys Acta. 2000 Oct 31;1488(1-2):167-81
references.pmid: 11080686
references.citation: Endocrinology. 2009 Jun;150(6):2569-76
references.pmid: 19246537
references.citation: Cell. 1993 Oct 22;75(2):241-51
references.pmid: 7503812
references.citation: Lipids. 2001 Jul;36(7):689-700
references.pmid: 11521967
references.citation: J Biol Chem. 1998 May 8;273(19):11401-4
references.pmid: 9565547
references.citation: Prog Lipid Res. 2000 May;39(3):257-88
references.pmid: 10799718
references.citation: Clin Exp Immunol. 1983 Jan;51(1):1-7
references.pmid: 6339122
references.citation: Mol Endocrinol. 2005 Feb;19(2):504-15
references.pmid: 15471944
references.citation: Nature. 2001 Dec 13;414(6865):792-8
references.pmid: 11742411
references.citation: J Immunol. 1978 Apr;120(4):1375-7
references.pmid: 347001
references.citation: J Clin Invest. 2003 Dec;112(12):1831-42
references.pmid: 14679178
references.citation: Biochem Biophys Res Commun. 2000 Dec 20;279(2):378-82
references.pmid: 11118295
references.citation: Proc Natl Acad Sci U S A. 1995 Aug 29;92(18):8527-31
references.pmid: 7667324
references.citation: Mol Cell. 2004 May 7;14(3):277-87
references.pmid: 15125832
references.citation: J Biol Chem. 2006 Jul 28;281(30):20958-20973
references.pmid: 16732058
references.citation: Methods Mol Biol. 1998;108:107-10
references.pmid: 9921520
references.citation: Nature. 2001 Dec 13;414(6865):807-12
references.pmid: 11742413
references.citation: Nat Genet. 1996 Apr;12(4):385-9
references.pmid: 8630491
references.citation: Science. 2005 Jan 21;307(5708):384-7
references.pmid: 15662004
references.citation: Am J Clin Nutr. 1991 Nov;54(5):846-54
references.pmid: 1951155
references.citation: Cell Death Differ. 2007 Jul;14(7):1243-7
references.pmid: 17431425
references.citation: Proc Natl Acad Sci U S A. 2002 Feb 5;99(3):1259-63
references.pmid: 11818574
references.citation: Life Sci. 2009 May 8;84(19-20):688-95
references.pmid: 19250943
references.citation: Biochemistry. 2007 Sep 4;46(35):10170-85
references.pmid: 17685585
references.citation: J Biol Chem. 2008 Dec 12;283(50):34819-32
references.pmid: 18936091
references.citation: Diabetes. 2003 Jan;52(1):102-10
references.pmid: 12502499
references.citation: Annu Rev Nutr. 1985;5:365-90
references.pmid: 2992549