Cellular Respiration Bioenergetics

我们假设线粒体氧化代谢决定了创伤应激后高能量储存和器官功能的恢复。线粒体功能障碍导致能量产生受损，刺激氧化诱导的炎症并促进细胞凋亡。在创伤后应激中重要的炎症因子包括溶血磷脂（LPC）（项目IV-Moore和项目V-Meng）和肿瘤坏死α (tnf - α)（项目VII-Harken）等介质。这些介质不仅可以诱导线粒体功能障碍，但我们认为线粒体失调本身启动炎症级联反应。多系统器官功能障碍（MOD）与氧气消耗受损有关（IA-Offner项目）。我们已经报道了严重损伤的MOD患者表现出线粒体细胞色素a， a3（细胞色素c氧化酶）与组织氧合血红蛋白氧化还原状态的早期解耦。线粒体呼吸的这种解耦与细胞氧化剂的产生有关，并提供了严重创伤后线粒体电子传递固有缺陷的证据。我们的初步研究表明，在创伤后应激状态下，线粒体电子传递可以被治疗性地操纵，从而减少氧化剂的产生，炎症介质的产生并改善器官功能。然而，线粒体对治疗手段的反应能力可能受到线粒体结构和分布的固有改变的影响（项目VIII-Banerjee）。此外，线粒体基因组是氧化损伤的目标，这可能导致不可逆损伤的发展和功能障碍的延续（与IB-Johnson项目）。总体假设：创伤后应激因素（缺血、缺氧、炎症）使细胞色素c氧化酶与组织氧合血红蛋白脱钩，改变线粒体形态、分布、电子传递和膜电位。旨在稳定细胞色素c氧化酶和防止线粒体形态改变的疗法将调节氧化信号，过度炎症并优化创伤后应激期间体内线粒体呼吸。

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.