The Role of the Mitochondrion in the Metabolic Stress Response to Burn Trauma

项目摘要 体内能量转换的效率对体重调节和 健康线粒体质子泄漏，这是一个过程，其中由线粒体通过线粒体产生的质子梯度， 衬底的氧化和电子转移被转换成热，而不是被利用来产生 ATP是哺乳动物代谢效率低下的主要原因。体温调节是主要的 归因于线粒体质子泄漏的生理作用，其负责约20-25%的解偶联 线粒体呼吸产生ATP。 人们对线粒体质子泄漏的假定抗肥胖作用非常感兴趣。这是由 通过相对较新的观察发现一些成年人具有功能性棕色脂肪组织（BAT）， 并且在某些应激状态下，皮下白色脂肪组织（scWAT）可经历布朗宁 响应，发展一些BAT特征。BAT线粒体的独特之处在于它们表达了 膜载体蛋白UCP 1（解偶联蛋白1）。UCP 1介导的质子泄漏几乎可以完全 解开BAT线粒体，燃料氧化和呼吸可以不受抑制地进行， ATP的生产。在长时间冷应激的啮齿动物模型中，UCP 1介导的BAT和scWAT中的质子泄漏 会显著影响新陈代谢率和体重。然而，线粒体质子泄漏的作用， 对慢性冷暴露模型之外的代谢调节仍然知之甚少。 我们提出了一系列创新的研究，利用严重烧伤作为一个独特的临床模型， 高代谢（代谢率增加），以探讨线粒体质子泄漏在调节 代谢率和体重。我们的总体假设是UCP 1介导的质子泄漏在两个BAT 和scWAT有助于烧伤诱导的高代谢。在具体目标1中，我们将进一步了解 高代谢的生化基础，通过确定线粒体的组织特异性贡献， 质子泄漏烧伤引起的高代谢，同时也确定这些质子的分子转换器 漏水此外，稳定同位素研究将用于确定ATP依赖性底物循环的作用 在scWAT作为一种新的UCP 1独立的脂肪细胞产热机制。具体目标2： 研究肥胖和BAT激活和scWAT布朗宁能力降低对烧伤的影响。 引起高代谢。具体来说，我们将确定磷脂和载体的关键变化 蛋白质组成的线粒体膜在肝脏和骨骼肌，以确定关键 线粒体质子泄漏超出UCP 1的调节剂。这一新知识可能具有临床价值， 鉴定可被调节以在高代谢的情况下降低代谢率的靶标，或 在营养过度供应和肥胖的情况下增加线粒体效率低下。

PROJECT SUMMARY The efficiency of energy transduction in the body has significant implications for body weight regulation and health. Mitochondrial proton leaks, a process where the proton gradient generated by mitochondria through the oxidation of substrates and electron transfer is transduced to heat rather than being harnessed to generate ATP, is a major contributor to metabolic inefficiency in mammals. Thermoregulation is the principal physiological role ascribed to mitochondria proton leaks, which are responsible for uncoupling around 20-25% of mitochondrial respiration for ATP production. There is significant interest in a putative anti-obesity role for mitochondrial proton leaks. This has been driven by the relatively recent observation that some adult humans possess functional brown adipose tissue (BAT), and that under certain stress states, subcutaneous white adipose tissue (scWAT) can undergo a browning response, developing some BAT characteristics. BAT mitochondria are unique in that they express the inner membrane carrier protein UCP1 (uncoupling protein 1). UCP1-mediated proton leak can almost completely uncouple BAT mitochondria, where fuel oxidation and respiration can proceed uninhibited and in the absence of ATP production. In rodent models of prolonged cold stress, UCP1-mediated proton leak in BAT and scWAT can significantly influence metabolic rate and body mass. However, the role of mitochondrial proton leaks in metabolic regulation beyond models of chronic cold exposure remains poorly understood. We propose a series of innovative studies leveraging severe burn injury as a unique clinical model of hypermetabolism (increased metabolic rate) to probe the role of mitochondrial proton leaks in the regulation of metabolic rate and body mass. Our overarching hypothesis is that UCP1-mediated proton leak in both BAT and scWAT contribute to burn-induced hypermetabolism. In specific aim 1, we will further our understanding of the biochemical basis of hypermetabolism by identifying the tissue specific contributions of mitochondrial proton leaks to burn-induced hypermetabolism, while also identifying the molecular transducers of these proton leaks. In addition, stable isotope studies will be used to determine the role of ATP dependent substrate cycling within scWAT as a novel UCP1-independent mechanism of adipocyte thermogenesis. In specific aim 2, we will investigate the impact of obesity and diminished capacity of BAT activation and scWAT browning on burn- induced hypermetabolism. Specifically, we will determine the key changes in the phospholipid and carrier protein composition of mitochondrial membranes in the liver and skeletal muscle in order to identify key modulators of mitochondrial proton leak beyond UCP1. This new knowledge may hold clinical value in terms of identifying targets that may be modulated either to reduce metabolic rate in the context of hypermetabolism, or to augment mitochondrial inefficiency in the context of nutrient over-supply and obesity.