We postulate that mitochondrial oxidative metabolism determines restoration of high energy stores and organ function after traumatic stress sites. Mitochondrial dysfunction leads to impaired energy production, stimulates oxidant induced inflammation and promotes apoptosis. Inflammatory agents important in post-traumatic stress includes mediators such as lysophospholipids (LPC) (with projects IV-Moore and project V-Meng) and tumor necrosis alpha (TNF-alpha) (with project VII-Harken). Not only can these mediators induce mitochondrial dysfunction, but we propose that dysregulated mitochondrial themselves initiate the inflammatory cascade. Multi-system organ dysfunction (MOD) is associated with impaired oxygen consumption (with project IA-Offner). We have reported that severely injured patients who develop MOD exhibit an early decoupling of the redox state of mitochondrial cytochrome a, a3 (cytochrome c oxidase) from tissue oxyhemoglobin. This decoupling of mitochondrial respiration is associated with the production of cellular oxidants and provides evidence of an inherent defect in mitochondrial electron transport after severe traumatic injury. Our preliminary studies suggest that mitochondrial electron transport can be therapeutically manipulated in post-traumatic stress states, resulting in reduced oxidant production, inflammatory mediator generation and improving organ function. Yet, the capacity for mitochondria to respond to therapeutic maneuvers may be influenced by inherent alterations in mitochondrial structure and distribution (with project VIII-Banerjee). Further, the mitochondrial genome is a target of oxidative damage which may lead to the development of irreversible injury and the perpetuation of dysfunction (with project IB-Johnson). Global Hypothesis: Post-traumatic stressors (ischemia, hypoxia, inflammation) decouple cytochrome c oxidase from tissue oxyhemoglobin, alter mitochondrial morphology, distribution, electron transport and membrane potential. Therapies designed to stabilize cytochrome c oxidase and to prevent mitochondrial morphologic alterations will modulate oxidant signaling, hyperinflammation and optimize in vivo mitochondrial respiration during post-traumatic stress.
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