title: Mitochondrial oscillations and waves in cardiac myocytes: insights from computational models.
abstract: 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.
authors.affiliation: Department of Medicine (Cardiology), David Geffen School of Medicine at University of California, Los Angeles, California, USA.
authors.forename: Ling
authors.initials: L
authors.lastname: Yang
authors.forename: Paavo
authors.initials: P
authors.lastname: Korge
authors.forename: James N
authors.initials: JN
authors.lastname: Weiss
authors.forename: Zhilin
authors.initials: Z
authors.lastname: Qu
mesh_terms: 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
chemical_list: D007473:Ion Channels; D033681:Mitochondrial Membrane Transport Proteins; D000083162:Mitochondrial Permeability Transition Pore; D017382:Reactive Oxygen Species
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