title: Oxidant-induced inhibition of the plasma membrane Ca2+-ATPase in pancreatic acinar cells: role of the mitochondria.
abstract: Impairment of the normal spatiotemporal pattern of intracellular Ca(2+) ([Ca(2+)](i)) signaling, and in particular, the transition to an irreversible "Ca(2+) overload" response, has been implicated in various pathophysiological states. In some diseases, including pancreatitis, oxidative stress has been suggested to mediate this Ca(2+) overload and the associated cell injury. We have previously demonstrated that oxidative stress with hydrogen peroxide (H(2)O(2)) evokes a Ca(2+) overload response and inhibition of plasma membrane Ca(2+)-ATPase (PMCA) in rat pancreatic acinar cells (Bruce JI and Elliott AC. Am J Physiol Cell Physiol 293: C938-C950, 2007). The aim of the present study was to further examine this oxidant-impaired inhibition of the PMCA, focusing on the role of the mitochondria. Using a [Ca(2+)](i) clearance assay in which mitochondrial Ca(2+) uptake was blocked with Ru-360, H(2)O(2) (50 microM-1 mM) markedly inhibited the PMCA activity. This H(2)O(2)-induced inhibition of the PMCA correlated with mitochondrial depolarization (assessed using tetramethylrhodamine methylester fluorescence) but could occur without significant ATP depletion (assessed using Magnesium Green fluorescence). The H(2)O(2)-induced PMCA inhibition was sensitive to the mitochondrial permeability transition pore (mPTP) inhibitors, cyclosporin-A and bongkrekic acid. These data suggest that oxidant-induced opening of the mPTP and mitochondrial depolarization may lead to an inhibition of the PMCA that is independent of mitochondrial Ca(2+) handling and ATP depletion, and we speculate that this may involve the release of a mitochondrial factor. Such a phenomenon may be responsible for the Ca(2+) overload response, and for the transition between apoptotic and necrotic cell death thought to be important in many disease states.
authors.affiliation: Faculty of Life Sciences, 2nd Floor Core Technology Facility, 46 Grafton St., Univ. of Manchester, Manchester M13 9NT, UK.
authors.forename: Erin M
authors.initials: EM
authors.lastname: Baggaley
authors.forename: Austin C
authors.initials: AC
authors.lastname: Elliott
authors.forename: Jason I E
authors.initials: JI
authors.lastname: Bruce
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D000968:Antimycin A / Q000494:pharmacology; D001681:Biological Assay; D001865:Bongkrekic Acid / Q000494:pharmacology; D020013:Calcium Signaling / Q000187:drug effects; D002258:Carbonyl Cyanide m-Chlorophenyl Hydrazone / Q000494:pharmacology; D016572:Cyclosporine / Q000494:pharmacology; D006861:Hydrogen Peroxide / Q000378:metabolism; D053078:Membrane Potential, Mitochondrial; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism*; D033681:Mitochondrial Membrane Transport Proteins / Q000378:metabolism; D000083162:Mitochondrial Permeability Transition Pore; D009840:Oligomycins / Q000494:pharmacology; D018384:Oxidative Stress / Q000187:drug effects; D046790:Pancreas, Exocrine / Q000187:drug effects / Q000201:enzymology*; D053499:Plasma Membrane Calcium-Transporting ATPases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D015203:Reproducibility of Results; D017975:Ruthenium Compounds / Q000494:pharmacology; D013997:Time Factors; D014475:Uncoupling Agents / Q000494:pharmacology
chemical_list: D033681:Mitochondrial Membrane Transport Proteins; D000083162:Mitochondrial Permeability Transition Pore; D009840:Oligomycins; C112020:Ru 360; D017975:Ruthenium Compounds; D014475:Uncoupling Agents; D001865:Bongkrekic Acid; D002258:Carbonyl Cyanide m-Chlorophenyl Hydrazone; D000968:Antimycin A; D016572:Cyclosporine; D000255:Adenosine Triphosphate; D006861:Hydrogen Peroxide; D053499:Plasma Membrane Calcium-Transporting ATPases
references.citation: Mol Cell Biochem. 2005 Jan;269(1-2):165-73
references.pmid: 15786729
references.citation: Nat Rev Mol Cell Biol. 2003 Jul;4(7):552-65
references.pmid: 12838338
references.citation: J Physiol. 2000 Nov 15;529 Pt 1:57-68
references.pmid: 11080251
references.citation: Free Radic Biol Med. 1999 Oct;27(7-8):810-21
references.pmid: 10515585
references.citation: Cell Calcium. 1986 Feb;7(1):1-12
references.pmid: 2420465
references.citation: J Biol Chem. 1981 Aug 25;256(16):8588-92
references.pmid: 6455424
references.citation: Biochemistry. 2007 Jan 30;46(4):1034-41
references.pmid: 17240987
references.citation: J Biol Chem. 1997 Jul 18;272(29):17981-6
references.pmid: 9218424
references.citation: Gastroenterology. 2003 Feb;124(2):494-503
references.pmid: 12557154
references.citation: J Biol Chem. 2007 Dec 28;282(52):37678-93
references.pmid: 17938178
references.citation: J Cell Biol. 2004 Jul 19;166(2):193-203
references.pmid: 15263017
references.citation: Nat Cell Biol. 2000 Mar;2(3):E41-3
references.pmid: 10707095
references.citation: J Biol Chem. 2002 Dec 13;277(50):48172-81
references.pmid: 12368283
references.citation: Biochim Biophys Acta. 1989 Jul 6;996(3):153-9
references.pmid: 2526658
references.citation: J Physiol. 2002 Feb 15;539(Pt 1):145-55
references.pmid: 11850508
references.citation: Cell Calcium. 2007 Aug;42(2):173-82
references.pmid: 17602740
references.citation: Pflugers Arch. 2008 Mar;455(6):1025-39
references.pmid: 17952455
references.citation: Free Radic Biol Med. 2003 Jul 1;35(1):1-8
references.pmid: 12826250
references.citation: J Physiol. 2002 Jun 15;541(Pt 3):877-94
references.pmid: 12068047
references.citation: J Biol Chem. 1988 Feb 5;263(4):1665-75
references.pmid: 3338986
references.citation: Biochemistry. 1994 Apr 19;33(15):4527-32
references.pmid: 8161507
references.citation: FASEB J. 1989 Sep;3(11):2298-301
references.pmid: 2528493
references.citation: Am J Physiol Gastrointest Liver Physiol. 2004 Feb;286(2):G189-96
references.pmid: 14715516
references.citation: Biochem J. 1999 Jul 15;341 ( Pt 2):233-49
references.pmid: 10393078
references.citation: Biochim Biophys Acta. 1990 Aug 10;1027(1):41-6
references.pmid: 2168752
references.citation: Nat Cell Biol. 2003 Dec;5(12):1051-61
references.pmid: 14608362
references.citation: Oncogene. 1998 Oct 15;17(15):1903-10
references.pmid: 9788433
references.citation: Cell Tissue Res. 2003 Jul;313(1):37-45
references.pmid: 12838407
references.citation: J Biol Chem. 2004 Mar 26;279(13):12909-17
references.pmid: 14699167
references.citation: Nature. 2005 Mar 31;434(7033):658-62
references.pmid: 15800627
references.citation: Proc Natl Acad Sci U S A. 2005 Jan 4;102(1):105-10
references.pmid: 15613488
references.citation: J Gen Physiol. 2000 Oct;116(4):547-60
references.pmid: 11004204
references.citation: J Biol Chem. 2004 Nov 19;279(47):49064-73
references.pmid: 15317809
references.citation: Physiol Rev. 1991 Jan;71(1):129-53
references.pmid: 1986387
references.citation: Trends Pharmacol Sci. 2006 Feb;27(2):113-20
references.pmid: 16406087
references.citation: Gastroenterology. 2006 Mar;130(3):781-93
references.pmid: 16530519
references.citation: J Physiol. 1996 Oct 1;496 ( Pt 1):111-28
references.pmid: 8910200
references.citation: Physiol Rev. 1997 Oct;77(4):901-30
references.pmid: 9354808
references.citation: J Biol Chem. 1999 Jul 16;274(29):20561-8
references.pmid: 10400686
references.citation: EMBO J. 1999 Sep 15;18(18):4999-5008
references.pmid: 10487752
references.citation: Cell Calcium. 2002 Aug;32(2):59-69
references.pmid: 12161106
references.citation: J Biol Chem. 1989 May 15;264(14):7826-30
references.pmid: 2470734
references.citation: Immunopharmacology. 2000 May;47(2-3):119-25
references.pmid: 10878286
references.citation: J Gen Physiol. 1995 Feb;105(2):209-26
references.pmid: 7760017
references.citation: Mol Aspects Med. 2004 Aug;25(4):365-451
references.pmid: 15302203
references.citation: EMBO J. 2002 Dec 16;21(24):6744-54
references.pmid: 12485995
references.citation: Pancreatology. 2007;7(5-6):436-46
references.pmid: 17898533
references.citation: Cell Death Differ. 2006 Oct;13(10):1675-85
references.pmid: 16410794
references.citation: Cell Death Differ. 2003 Jun;10(6):687-97
references.pmid: 12761577
references.citation: Proc Natl Acad Sci U S A. 2007 Mar 27;104(13):5674-9
references.pmid: 17363470
references.citation: Physiology (Bethesda). 2006 Aug;21:242-9
references.pmid: 16868313
references.citation: Cell Death Differ. 2002 Mar;9(3):234-6
references.pmid: 11859405
references.citation: Cell Death Differ. 2005 May;12(5):453-62
references.pmid: 15933725
references.citation: J Membr Biol. 1988 May;102(2):153-62
references.pmid: 2458473
references.citation: Am J Physiol Cell Physiol. 2007 Sep;293(3):C938-50
references.pmid: 17494627
references.citation: J Biol Chem. 1989 Apr 5;264(10):5622-7
references.pmid: 2925624
references.citation: J Biol Chem. 2001 Jul 13;276(28):26411-20
references.pmid: 11333261
references.citation: Nat Cell Biol. 2005 Oct;7(10):1021-8
references.pmid: 16179951
references.citation: Biochim Biophys Acta. 1978 Aug 4;511(2):194-201
references.pmid: 150288
references.citation: J Cell Sci. 2002 Feb 1;115(Pt 3):485-97
references.pmid: 11861756