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A Mitochondrial Oscillator Dependent on Reactive Oxygen Species

The Johns Hopkins University, Institute of Molecular Cardiobiology and Center for Cardiovascular Bioinformatics and Modeling, Baltimore, Maryland

Correspondence: Address reprint requests to Brian O'Rourke, PhD, The Johns Hopkins University, Institute of Molecular Cardiobiology, 720 Rutland Ave., 844 Ross Bldg., Baltimore, MD 21205-2195. Tel.: 410-614-0034; Fax: 410-955-7953; E-mail: bor{at}jhmi.edu.

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 (_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 Ca²⁺ 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 _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.

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