title: From mitochondrial dynamics to arrhythmias.
abstract: The reactive oxygen species (ROS)-dependent mitochondrial oscillator described in cardiac cells exhibits at least two modes of function under physiological conditions or in response to metabolic and oxidative stress. Both modes depend upon network behavior of mitochondria. Under physiological conditions cardiac mitochondria behave as a network of coupled oscillators with a broad range of frequencies. ROS weakly couples mitochondria under normal conditions but becomes a strong coupling messenger when, under oxidative stress, the mitochondrial network attains criticality. Mitochondrial criticality is achieved when a threshold of ROS is overcome and a certain density of mitochondria forms a cluster that spans the whole cell. Under these conditions, the slightest perturbation triggers a cell-wide collapse of the mitochondrial membrane potential, Delta psi(m), visualized as a depolarization wave throughout the cell which is followed by whole cell synchronized oscillations in Delta psi(m), NADH, ROS, and GSH. This dynamic behavior scales from the mitochondrion to the cell by driving cellular excitability and the whole heart into catastrophic arrhythmias. A network collapse of Delta psi(m) under criticality leads to: (i) energetic failure, (ii) temporal and regional alterations in action potential (AP), (iii) development of zones of impaired conduction in the myocardium, and, ultimately, (iv) a fatal ventricular arrhythmia.
authors.affiliation: Johns Hopkins University, School of Medicine, Division of Cardiology, 720 Rutland Ave., 1059 Ross Bldg., Baltimore, MD 21205, USA. maon1@jhmi.edu
authors.forename: M A
authors.initials: MA
authors.lastname: Aon
authors.forename: S
authors.initials: S
authors.lastname: Cortassa
authors.forename: F G
authors.initials: FG
authors.lastname: Akar
authors.forename: D A
authors.initials: DA
authors.lastname: Brown
authors.forename: L
authors.initials: L
authors.lastname: Zhou
authors.forename: B
authors.initials: B
authors.lastname: O'Rourke
mesh_terms: D000818:Animals; D001145:Arrhythmias, Cardiac / Q000209:etiology* / Q000378:metabolism*; D006801:Humans; D053078:Membrane Potential, Mitochondrial / Q000502:physiology; D008564:Membrane Potentials / Q000502:physiology; D008929:Mitochondria, Heart / Q000378:metabolism / Q000502:physiology*; D018384:Oxidative Stress / Q000502:physiology; D017382:Reactive Oxygen Species / Q000378:metabolism
chemical_list: D017382:Reactive Oxygen Species
references.citation: Proc Natl Acad Sci U S A. 1998 Jan 20;95(2):510-4
references.pmid: 9435222
references.citation: Physiol Rev. 2004 Apr;84(2):431-88
references.pmid: 15044680
references.citation: Biochim Biophys Acta. 2006 Feb;1762(2):232-40
references.pmid: 16242921
references.citation: Novartis Found Symp. 2007;287:140-51; discussion 152-6
references.pmid: 18074636
references.citation: Biophys J. 2006 Dec 1;91(11):4317-27
references.pmid: 16980364
references.citation: J Physiol. 1999 Apr 1;516 ( Pt 1):1-17
references.pmid: 10066918
references.citation: Biophys J. 2004 Sep;87(3):2022-34
references.pmid: 15345578
references.citation: Biochem Soc Symp. 1999;66:167-79
references.pmid: 10989666
references.citation: Proc Natl Acad Sci U S A. 2004 Mar 30;101(13):4447-52
references.pmid: 15070738
references.citation: Science. 1994 Aug 12;265(5174):962-6
references.pmid: 8052856
references.citation: J Clin Invest. 2005 Dec;115(12):3527-35
references.pmid: 16284648
references.citation: Adv Exp Med Biol. 2008;641:98-117
references.pmid: 18783175
references.citation: J Biol Chem. 2003 Nov 7;278(45):44735-44
references.pmid: 12930841
references.citation: J Biol Chem. 1989 Jan 25;264(3):1508-15
references.pmid: 2492277
references.citation: J Biol Chem. 2007 Jul 27;282(30):21889-900
references.pmid: 17540766
references.citation: Antioxid Redox Signal. 2006 Sep-Oct;8(9-10):1651-65
references.pmid: 16987019
references.citation: Biophys J. 2006 Aug 15;91(4):1564-89
references.pmid: 16679365
references.citation: Cardiovasc Res. 2008 Jan 15;77(2):334-43
references.pmid: 18006487
references.citation: J Biol Chem. 1987 Nov 5;262(31):15085-93
references.pmid: 2444594
references.citation: J Exp Med. 2000 Oct 2;192(7):1001-14
references.pmid: 11015441
references.citation: Cardiovasc Res. 2008 Jul 1;79(1):141-9
references.pmid: 18304929
references.citation: J Mol Cell Cardiol. 2008 Nov;45(5):650-60
references.pmid: 18760283
references.citation: Biophys J. 2004 Sep;87(3):2060-73
references.pmid: 15345581
references.citation: Cardiovasc Res. 2005 May 1;66(2):222-32
references.pmid: 15820191
references.citation: Proc Natl Acad Sci U S A. 2005 Jan 18;102(3):808-13
references.pmid: 15647364
references.citation: Biophys J. 2009 Oct 7;97(7):1843-52
references.pmid: 19804714
references.citation: Physiol Rev. 1999 Apr;79(2):609-34
references.pmid: 10221990
references.citation: Physiology (Bethesda). 2005 Oct;20:303-15
references.pmid: 16174870
references.citation: J Physiol. 2000 Nov 15;529 Pt 1:23-36
references.pmid: 11080248
references.citation: Arch Biochem Biophys. 2003 Dec 15;420(2):222-36
references.pmid: 14654061