title: Effects of mitochondrial uncoupling on Ca(2+) signaling during excitation-contraction coupling in atrial myocytes.
abstract: Mitochondria play an important role in intracellular Ca(2+) concentration ([Ca(2+)]i) regulation in the heart. We studied sarcoplasmic reticulum (SR) Ca(2+) release in cat atrial myocytes during depolarization of mitochondrial membrane potential (ΔΨm) induced by the protonophore FCCP. FCCP caused an initial decrease of action potential-induced Ca(2+) transient amplitude and frequency of spontaneous Ca(2+) waves followed by partial recovery despite partially depleted SR Ca(2+) stores. In the presence of oligomycin, FCCP only exerted a stimulatory effect on Ca(2+) transients and Ca(2+) wave frequency, suggesting that the inhibitory effect of FCCP was mediated by ATP consumption through reverse-mode operation of mitochondrial F1F0-ATPase. ΔΨm depolarization was accompanied by cytosolic acidification, increases of diastolic [Ca(2+)]i, intracellular Na(+) concentration ([Na(+)]i), and intracellular Mg(2+) concentration ([Mg(2+)]i), and a decrease of intracellular ATP concentration ([ATP]i); however, glycolytic ATP production partially compensated for the exhaustion of mitochondrial ATP supplies. In conclusion, the initial inhibition of Ca(2+) transients and waves resulted from suppression of ryanodine receptor SR Ca(2+) release channel activity by a decrease in [ATP], an increase of [Mg(2+)]i, and cytoplasmic acidification. The later stimulation resulted from reduced mitochondrial Ca(2+) buffering and cytosolic Na(+) and Ca(2+) accumulation, leading to enhanced Ca(2+)-induced Ca(2+) release and spontaneous Ca(2+) release in the form of Ca(2+) waves. ΔΨm depolarization and the ensuing consequences of mitochondrial uncoupling observed here (intracellular acidification, decrease of [ATP]i, increase of [Na(+)]i and [Mg(2+)]i, and Ca(2+) overload) are hallmarks of ischemia. These findings may therefore provide insight into the consequences of mitochondrial uncoupling for ion homeostasis, SR Ca(2+) release, and excitation-contraction coupling in ischemia at the cellular and subcellular level.
authors: Department of Cell and Molecular Physiology, Loyola University Chicago, Stritch School of Medicine, Maywood, IL, USA.
authors: Aleksey V
authors: AV
authors: Zima
authors: Malikarjuna R
authors: MR
authors: Pabbidi
authors: Stephen L
authors: SL
authors: Lipsius
authors: Lothar A
authors: LA
authors: Blatter
mesh_terms: D000200:Action Potentials / Q000187:drug effects; D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D002118:Calcium / Q000378:metabolism; D020013:Calcium Signaling / Q000187:drug effects*; D002259:Carbonyl Cyanide p-Trifluoromethoxyphenylhydrazone / Q000494:pharmacology; D002415:Cats; D003600:Cytosol / Q000378:metabolism; D056966:Excitation Contraction Coupling / Q000187:drug effects*; D006019:Glycolysis; D006325:Heart Atria / Q000166:cytology; D008274:Magnesium / Q000378:metabolism; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D008928:Mitochondria / Q000378:metabolism*; D032383:Myocytes, Cardiac / Q000378:metabolism* / Q000502:physiology; D009840:Oligomycins / Q000494:pharmacology; D010085:Oxidative Phosphorylation; D061209:Proton Ionophores / Q000494:pharmacology; D006180:Proton-Translocating ATPases / Q000378:metabolism; D012519:Sarcoplasmic Reticulum / Q000378:metabolism; D012964:Sodium / Q000378:metabolism; D014475:Uncoupling Agents / Q000494:pharmacology*
chemical_list: D009840:Oligomycins; D061209:Proton Ionophores; D014475:Uncoupling Agents; D002259:Carbonyl Cyanide p-Trifluoromethoxyphenylhydrazone; D000255:Adenosine Triphosphate; D012964:Sodium; D006180:Proton-Translocating ATPases; D008274:Magnesium; D002118:Calcium
references: Am J Physiol. 1989 Feb;256(2 Pt 2):H328-33
references: 2537030
references: Am J Physiol Cell Physiol. 2007 Jul;293(1):C106-18
references: 17344311
references: J Physiol. 2000 May 1;524 Pt 3:795-806
references: 10790159
references: J Physiol. 1996 Oct 1;496 ( Pt 1):111-28
references: 8910200
references: Biophys J. 2004 Aug;87(2):1360-8
references: 15298938
references: Physiol Rev. 2002 Oct;82(4):893-922
references: 12270947
references: Adv Exp Med Biol. 2012;942:249-67
references: 22399426
references: Pflugers Arch. 1990 Feb;415(5):645-7
references: 2158071
references: Pharmacol Res. 1999 Mar;39(3):167-74
references: 10094840
references: J Biol Chem. 1989 Apr 5;264(10):5622-7
references: 2925624
references: Pflugers Arch. 1989 Mar;413(5):553-8
references: 2740208
references: Cell Calcium. 1991 Feb-Mar;12(2-3):241-54
references: 2059996
references: Q J Exp Physiol. 1986 Jul;71(3):467-73
references: 3763808
references: J Physiol. 2003 Aug 1;550(Pt 3):765-83
references: 12824454
references: Circ Res. 1987 Feb;60(2):153-68
references: 3552284
references: J Mol Cell Cardiol. 1982 Sep;14 Suppl 3:13-20
references: 7143453
references: Circ Res. 1991 Jan;68(1):150-61
references: 1845852
references: Circulation. 1991 Feb;83(2):681-8
references: 1991384
references: J Biol Chem. 1987 Mar 5;262(7):3065-73
references: 2434495
references: J Mol Cell Cardiol. 1992 Jul;24(7):669-81
references: 1404407
references: Biophys J. 1986 Nov;50(5):1009-14
references: 2431724
references: Am J Physiol Heart Circ Physiol. 2012 Oct 15;303(8):H1047-56
references: 22904161
references: J Gen Physiol. 1989 Nov;94(5):911-35
references: 2512370
references: J Mol Cell Cardiol. 2009 Jun;46(6):767-74
references: 19162034
references: Circulation. 1997 Aug 19;96(4):1275-81
references: 9286959
references: Am J Physiol. 1994 Jan;266(1 Pt 1):C222-33
references: 8304418
references: Am J Physiol. 1983 Jul;245(1):C1-14
references: 6346892
references: Circ Res. 1996 Dec;79(6):1100-9
references: 8943948
references: J Physiol. 1984 Sep;354:3P-22P
references: 6434728
references: Circ Res. 1991 Apr;68(4):1059-69
references: 1706963
references: Biochem J. 2000 Apr 15;347(Pt 2):593-600
references: 10749691
references: Science. 1988 Oct 7;242(4875):99-102
references: 2459777
references: J Physiol. 2005 May 1;564(Pt 3):697-714
references: 15695247
references: Physiol Rev. 1981 Apr;61(2):296-434
references: 7012859
references: J Mol Cell Cardiol. 2012 Jan;52(1):48-61
references: 21964191
references: Circ Res. 1995 Jul;77(1):88-97
references: 7788886
references: J Physiol. 2002 Nov 15;545(1):65-79
references: 12433950
references: J Physiol. 2006 Nov 15;577(Pt 1):281-93
references: 16945967
references: J Physiol. 1996 Aug 1;494 ( Pt 3):641-51
references: 8865063
references: Annu Rev Med. 1990;41:231-8
references: 2184726
references: Cell Calcium. 2008 Jul;44(1):77-91
references: 18178248
references: Annu Rev Physiol. 1986;48:349-61
references: 3010816
references: J Physiol. 1995 May 1;484 ( Pt 3):605-16
references: 7623279
references: J Physiol. 2003 Jan 1;546(Pt 1):119-35
references: 12509483
references: Adv Exp Med Biol. 2012;740:217-34
references: 22453944
references: Heart Fail Rev. 2007 Dec;12(3-4):249-60
references: 17516167
references: Am J Physiol Cell Physiol. 2007 Jan;292(1):C137-47
references: 16971498
references: J Physiol. 2003 Jan 1;546(Pt 1):19-31
references: 12509476