The enormous energy demands of the heart require mitochondrial oxidative phosphorylation to be exquisitely sensitive to changes in cellular work, but also render mitochondria vulnerable to injury during times of metabolic stress. The overarching goal of our research has been to define the central role of mitochondrial ion channels in the mechanisms of cardiac cell death (involving inner membrane anion channels and the permeability transition pore) and in the protective mechanism of ischemic preconditioning (through the actions of mitochondrial K+ channels). Recently, we have elucidated a detailed mechanistic model of how mitochondria are organized as a network of oscillators, whose non-linear properties define how the energy state can change dramatically (manifested as oscillations or metabolic collapse) in response to a small perturbation when the system reaches a specific threshold. This critical behavior involves mitochondrially-derived reactive oxygen species (ROS), the inner membrane anion channel (IMAC), and the ROS scavenging capacity of the myocyte. We propose that this mechanism accounts for heterogeneity in the energetic and electrical recovery of individual cells or groups of cells in the post-ischemic heart. In this proposal, we will explore i) the factors controlling the non-linear dynamics of mitochondria, ii) whether the mitochondrial oscillator mechanism underlies arrhythmias and impaired contractile recovery upon reperfusion, and iii) whether physiological oscillations in mitochondrial ROS production constitute a signal transduction link between energetics and gene expression. Interpretation of the results will be informed by the next phase of development of an integrated computational model of the cardiac myocyte, incorporating the electrophysiological, excitation-contraction coupling, and energetic properties of the cell. This proposal addresses how the discoveries made during the prior funding period are implicated in the pathophysiology of cardiac ischemia-reperfusion injury, and how they may be applied therapeutically. ? ? ? ?
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