Mitochondrial Free Radical Production
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In this project, we codify the biochemical reaction network of mitochondrial energy and ROS metabolism and elucidate how this network operates in healthy and injured myocardium. In oxidative tissues such as the heart, mitochondria are essential for cellular viability. However, they play a dual role in a manner whereby even brief interruptions in oxidative phosphorylation may precipitate organ failure. These interruptions are caused by ischemia/reperfusion (IR) injury which leads to calcium (Ca2+) overload, disturbs reactive oxygen species (ROS) homeostasis, and impairs oxidative phosphorylation. The vast majority of mitochondrial ROS originate from the electron transport system (ETS). Under normal conditions, the ETS produces ROS at low rates; however, electron flow patterns can drastically alter when physiological conditions change (e.g., IR injury) causing ROS levels to surge. Unfortunately, therapeutic development is handicapped because we cannot causally link the underlying biochemical events (i.e., we cannot quantitatively predict these flow patterns in such disease states). To address this limitation, we will expand our recent ETS-ROS concept with new data focused on understanding what controls these flows. We will exploit the IR injury paradigm to develop, challenge, and verify our hypotheses and concepts where each aim is focused on a critical knowledge gap. We will step through a logical sequence of stages to generate novel data for model development, refinement, and validation at distinct spatiotemporal scales.
