Cellular Respiration Bioenergetics

我们推测，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，刺激氧化剂诱导的炎症，促进细胞凋亡。在创伤后应激中起重要作用的炎症介质包括溶血磷脂(LPC)(项目IV-Moore和项目V-Meng)和肿瘤坏死因子α(肿瘤坏死因子-α)(项目VII-Harken)。这些介质不仅可以导致线粒体功能障碍，而且我们认为，线粒体本身的失调启动了炎症级联反应。多系统器官功能障碍(MOD)与氧耗受损有关(IA-Offner项目)。我们已经报道，患有MOD的严重创伤患者表现出线粒体细胞色素a，A3(细胞色素c氧化酶)的氧化还原状态与组织氧合血红蛋白的早期脱偶。线粒体呼吸的这种解偶联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在治疗上得到控制，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，线粒体对治疗操作的反应能力可能会受到线粒体结构和分布固有变化的影响(项目VIII-Banerjee)。此外，线粒体基因组是氧化损伤的目标，氧化损伤可能导致不可逆转的损伤的发展和功能障碍的永久存在(IB-Johnson项目)。全球假说：创伤后应激源(缺血、缺氧、炎症)使细胞色素c氧化酶与组织氧合血红蛋白解偶联，改变线粒体的形态、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变化的治疗方法将在创伤后应激期间调节氧化信号、过度炎症和优化体内线粒体的呼吸。

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.