title: A mitochondrial oscillator dependent on reactive oxygen species.
abstract: We describe a unique mitochondrial oscillator that depends on oxidative phosphorylation, reactive oxygen species (ROS), and mitochondrial inner membrane ion channels. Cell-wide synchronized oscillations in mitochondrial membrane potential (Delta Psi(m)), NADH, and ROS production have been recently described in isolated cardiomyocytes, and we have hypothesized that the balance between superoxide anion efflux through inner membrane anion channels and the intracellular ROS scavenging capacity play a key role in the oscillatory mechanism. Here, we formally test the hypothesis using a computational model of mitochondrial energetics and Ca(2+) handling including mitochondrial ROS production, cytoplasmic ROS scavenging, and ROS activation of inner membrane anion flux. The mathematical model reproduces the period and phase of the observed oscillations in Delta Psi(m), NADH, and ROS. Moreover, we experimentally verify model predictions that the period of the oscillator can be modulated by altering the concentration of ROS scavengers or the rate of oxidative phosphorylation, and that the redox state of the glutathione pool oscillates. In addition to its role in cellular dysfunction during metabolic stress, the period of the oscillator can be shown to span a wide range, from milliseconds to hours, suggesting that it may also be a mechanism for physiological timekeeping and/or redox signaling.
authors.affiliation: The Johns Hopkins University, Institute of Molecular Cardiobiology and Center for Cardiovascular Bioinformatics and Modeling, Baltimore, Maryland 21205-2195, USA.
authors.forename: Sonia
authors.initials: S
authors.lastname: Cortassa
authors.forename: Miguel A
authors.initials: MA
authors.lastname: Aon
authors.forename: Raimond L
authors.initials: RL
authors.lastname: Winslow
authors.forename: Brian
authors.initials: B
authors.lastname: O'Rourke
mesh_terms: D000818:Animals; D002118:Calcium / Q000378:metabolism; D003600:Cytosol / Q000378:metabolism; D005978:Glutathione / Q000378:metabolism; D005979:Glutathione Peroxidase / Q000378:metabolism; D005980:Glutathione Reductase / Q000378:metabolism; D006168:Guinea Pigs; D006861:Hydrogen Peroxide / Q000737:chemistry; D007091:Image Processing, Computer-Assisted; D007700:Kinetics; D007834:Lasers; D008564:Membrane Potentials; D008856:Microscopy, Fluorescence / Q000379:methods*; D008928:Mitochondria / Q000378:metabolism*; D008954:Models, Biological; D008962:Models, Theoretical; D032383:Myocytes, Cardiac / Q000378:metabolism*; D009840:Oligomycins / Q000737:chemistry; D009991:Oscillometry; D010100:Oxygen / Q000378:metabolism; D017785:Photons; D017382:Reactive Oxygen Species; D015427:Reperfusion Injury; D013482:Superoxide Dismutase / Q000737:chemistry / Q000378:metabolism
chemical_list: D009840:Oligomycins; D017382:Reactive Oxygen Species; D006861:Hydrogen Peroxide; D005979:Glutathione Peroxidase; D013482:Superoxide Dismutase; D005980:Glutathione Reductase; D005978:Glutathione; D010100:Oxygen; D002118:Calcium