title: Synchronized whole cell oscillations in mitochondrial metabolism triggered by a local release of reactive oxygen species in cardiac myocytes.
abstract: Reactive oxygen species (ROS) and/or Ca2+ overload can trigger depolarization of mitochondrial inner membrane potential (DeltaPsim) and cell injury. Little is known about how loss of DeltaPsim in a small number of mitochondria might influence the overall function of the cell. Here we employ the narrow focal excitation volume of the two-photon microscope to examine the effect of local mitochondrial depolarization in guinea pig ventricular myocytes. Remarkably, a single local laser flash triggered synchronized and self-sustained oscillations in DeltaPsim, NADH, and ROS after a delay of approximately 40s, in more than 70% of the mitochondrial population. Oscillations were initiated only after a specific threshold level of mitochondrially produced ROS was exceeded, and did not involve the classical permeability transition pore or intracellular Ca2+ overload. The synchronized transitions were abolished by several respiratory inhibitors or a superoxide dismutase mimetic. Anion channel inhibitors potentiated matrix ROS accumulation in the flashed region, but blocked propagation to the rest of the myocyte, suggesting that an inner membrane, superoxide-permeable, anion channel opens in response to free radicals. The transitions in mitochondrial energetics were tightly coupled to activation of sarcolemmal KATP currents, causing oscillations in action potential duration, and thus might contribute to catastrophic arrhythmias during ischemia-reperfusion injury.
authors.affiliation: Johns Hopkins University, Institute of Molecular Cardiobiology, Baltimore, Maryland 21205-2195, USA.
authors.forename: Miguel A
authors.initials: MA
authors.lastname: Aon
authors.forename: Sonia
authors.initials: S
authors.lastname: Cortassa
authors.forename: Eduardo
authors.initials: E
authors.lastname: Marbán
authors.forename: Brian
authors.initials: B
authors.lastname: O'Rourke
mesh_terms: D000200:Action Potentials; D000818:Animals; D000838:Anions; D002118:Calcium / Q000378:metabolism; D002463:Cell Membrane Permeability; D004553:Electric Conductivity; D004734:Energy Metabolism; D006168:Guinea Pigs; D007425:Intracellular Membranes / Q000502:physiology; D007473:Ion Channels / Q000502:physiology; D008564:Membrane Potentials / Q000502:physiology; D008929:Mitochondria, Heart / Q000378:metabolism* / Q000648:ultrastructure; D032383:Myocytes, Cardiac / Q000648:ultrastructure*; D009243:NAD / Q000378:metabolism; D010507:Periodicity; D017382:Reactive Oxygen Species / Q000378:metabolism*; D012508:Sarcolemma / Q000502:physiology
chemical_list: D000838:Anions; D007473:Ion Channels; D017382:Reactive Oxygen Species; D009243:NAD; D002118:Calcium