Mitochondrial oscillations and waves in cardiac myocytes: insights from computational models.
Periodic cellwide depolarizations of mitochondrial membrane potential (PsiM) which are triggered by reactive oxygen species (ROS) and propagated by ROS-induced ROS release (RIRR) have been postulated to contribute to cardiac arrhythmogenesis and injury during ischemia/reperfusion. Two different modes of RIRR have been described: PsiM oscillations involving ROS-sensitive mitochondrial inner membrane anion channels (IMAC), and slow depolarization waves related to mitochondrial permeability transition pore (MPTP) opening. In this study, we developed a computational model of mitochondria exhibiting both IMAC-mediated RIRR and MPTP-mediated RIRR, diffusively coupled in a spatially extended network, to study the spatiotemporal dynamics of RIRR on PsiM. Our major findings are: 1), as the rate of ROS production increases, mitochondria can exhibit either oscillatory dynamics facilitated by IMAC opening, or bistable dynamics facilitated by MPTP opening; 2), in a diffusively-coupled mitochondrial network, the oscillatory dynamics of IMAC-mediated RIRR results in rapidly propagating (approximately 25 microm/s) cellwide PsiM oscillations, whereas the bistable dynamics of MPTP-mediated RIRR results in slow (0.1-2 microm/s) PsiM depolarization waves; and 3), the slow velocity of the MPTP-mediated depolarization wave is related to competition between ROS scavenging systems and ROS diffusion. Our observations provide mechanistic insights into the spatiotemporal dynamics underlying RIRR-induced PsiM oscillations and waves observed experimentally in cardiac myocytes.
Yang
Ling
L
Department of Medicine (Cardiology), David Geffen School of Medicine at University of California, Los Angeles, California, USA.
Korge
Paavo
P
Weiss
James N
JN
Qu
Zhilin
Z
D000818:Animals; D003198:Computer Simulation; D007473:Ion Channels / Q000378:metabolism; D053078:Membrane Potential, Mitochondrial; D008928:Mitochondria / Q000378:metabolism*; D033681:Mitochondrial Membrane Transport Proteins / Q000378:metabolism; D051336:Mitochondrial Membranes / Q000378:metabolism; D000083162:Mitochondrial Permeability Transition Pore; D008954:Models, Biological; D032383:Myocytes, Cardiac / Q000378:metabolism*; D017382:Reactive Oxygen Species / Q000378:metabolism; D013997:Time Factors
D007473:Ion Channels; D033681:Mitochondrial Membrane Transport Proteins; D000083162:Mitochondrial Permeability Transition Pore; D017382:Reactive Oxygen Species
J Lipid Res. 2006 Nov;47(11):2355-66
16946414
Biophys J. 2003 Apr;84(4):2734-55
12668482
J Biol Chem. 1997 Aug 1;272(31):19282-9
9235923
Biochim Biophys Acta. 2006 Feb;1762(2):232-40
16242921
Arch Biochem Biophys. 1985 Mar;237(2):408-14
2983613
Free Radic Biol Med. 2000 Aug;29(3-4):222-30
11035250
J Exp Med. 2000 Oct 2;192(7):1001-14
11015441
Am J Physiol Cell Physiol. 2008 Feb;294(2):C460-6
18077608
Proc Natl Acad Sci U S A. 2004 Mar 30;101(13):4447-52
15070738
Biophys J. 2004 Sep;87(3):2060-73
15345581
J Biol Chem. 2004 Apr 23;279(17):17197-204
14963044
J Theor Biol. 2006 Oct 21;242(4):801-17
16814324
J Physiol. 2003 Oct 15;552(Pt 2):335-44
14561818
Ann N Y Acad Sci. 2005 Jun;1047:248-58
16093501
J Biol Chem. 2007 Jul 27;282(30):21889-900
17540766
Am J Physiol Cell Physiol. 2007 Sep;293(3):C815-29
17581855
Am J Physiol Heart Circ Physiol. 2006 Sep;291(3):H1036-46
16603683
Biophys J. 2006 Dec 1;91(11):4317-27
16980364
J Biol Chem. 2002 Nov 8;277(45):42563-71
12200425
Biochem J. 1999 Oct 15;343 Pt 2:311-7
10510294
Antioxid Redox Signal. 2006 Sep-Oct;8(9-10):1651-65
16987019
Biochim Biophys Acta. 2006 May-Jun;1757(5-6):509-17
16829228
Biophys J. 2004 Sep;87(3):2022-34
15345578
Physiol Rev. 2005 Jul;85(3):1093-129
15987803
Science. 2003 Jan 31;299(5607):700-4
12560550
J Physiol. 2008 Jul 1;586(13):3267-85
18467367
J Biol Chem. 2003 Nov 7;278(45):44735-44
12930841
J Biol Chem. 2008 Dec 26;283(52):36321-7
18948270
Curr Opin Cell Biol. 2003 Apr;15(2):221-31
12648679
Cell. 2008 Jul 25;134(2):279-90
18662543
J Biol Chem. 2007 Aug 24;282(34):24525-37
17591785
J Physiol. 2006 Mar 1;571(Pt 2):253-73
16410283
J Biol Chem. 1966 Jan 10;241(1):115-21
5901042
Am J Physiol Heart Circ Physiol. 2005 May;288(5):H2400-11
15681693