Molecular Aspects of Uncoupling Proteins

哺乳动物线粒体解偶联蛋白(UCPs)的分子相互作用和生物物理特性是本研究的重点。到目前为止，已在哺乳动物组织中发现了5个UCPs，其中3个(神经元型UCP2、4和5)广泛分布于中枢神经系统。这些有趣的蛋白质位于不同哺乳动物组织的线粒体内膜上，作为抗氧化剂，通过将电子传递过程与ATP的合成解偶联来干扰线粒体的呼吸。线粒体是三磷酸腺苷的主要生产者，三磷酸腺苷是维持生命的细胞能量的来源。矛盾的是，线粒体也是过量活性氧(ROS)的重要来源，ROS对线粒体和细胞都是有害的。线粒体功能障碍被认为是导致脑组织神经变性、创伤后死亡和衰老的主要原因之一。人们普遍认为，UCPs可以通过其解偶联功能减少ROS的产生。除了UCPs在氧化应激反应中的抗氧化作用外，它们还参与癌症、2型糖尿病、炎症过程和激活抗肥胖机制。尽管这些被认为具有重要的生理作用，但除了在幼年哺乳动物的体温调节中已确定的典型UCP1(广泛存在于棕色脂肪组织中)之外，人们对其他哺乳动物UCPs的结构和生物学功能的详细机制知之甚少。因此，有必要进行一项全面的分子研究，以揭开UCPs在不同组织中的不同生理作用的一些悬而未决的问题。拟议的研究计划将是我实验室现有的成熟研究计划的继续，并将集中在：(I)线粒体模型膜中神经元解偶联蛋白的结构和分子相互作用；(Ii)神经元UCPs中质子和阴离子运输的机制；以及(Iii)神经元UCPs在中枢神经系统氧化应激调节和神经保护中的作用。提出的研究计划是跨学科的，将不同的结构分析方法与光谱、电生理和分子建模技术相结合，探索神经元UCP结构与功能关系的分子基础。这一生物物理研究的结果对于理解线粒体的功能/功能障碍的机制及其在健康和疾病中的作用具有重要的意义。

Molecular interactions and biophysical characterization of mammalian mitochondrial uncoupling proteins (UCPs) are the focuses of this research program. So far, five UCPs have been discovered in mammalian tissues, three of which (neuronal UCPs 2, 4 and 5) are widely distributed in the central nervous system. These intriguing proteins are located in the inner membrane of the mitochondria of different mammalian tissues and, acting as antioxidants, disrupt the mitochondrial respiration by uncoupling the electron transport process from the synthesis of ATP. Mitochondria are the main producers of ATP, which is the source of cellular energy for maintenance of life. Paradoxically, mitochondria are also important sources of excessive reactive oxygen species (ROS), which are deleterious to both mitochondria and cells. Damaged dysfunctional mitochondria are considered to be one of the main causes of neurodegeneration of brain tissues, posttraumatic death, and ageing. It has been widely suggested that UCPs can reduce ROS production through their uncoupling function. In addition to the antioxidant role of UCPs in response to oxidative stress, their involvement in cancer, type 2 diabetes, inflammatory processes and activation of antiobesity mechanism have been suggested. Despite these suggested significant physiological roles, apart from the established role of the prototypical UCP1 (widely found in brown adipose tissues) in regulating the body temperature in young mammals, limited information is known about the details of structures and mechanisms of the biological function of other mammalian UCPs. A comprehensive molecular study is therefore necessary to unravel some of the unanswered questions about the diverse physiological roles of UCPs in different tissues. The proposed research program will be a continuation of an existing well-established research program in my laboratory and will concentrate on: (i) the structures and molecular interactions of the neuronal uncoupling proteins in mitochondrial model membranes; (ii) the mechanisms of proton and anion transport in neuronal UCPs; and (iii) the role of neuronal UCPs in regulation of oxidative stress and neuroprotection in the central nervous system. The proposed research program is interdisciplinary, and combines different methods of structural analysis with spectroscopic, electrophysiological and molecular modeling techniques to explore the molecular basis of the structure-function relationships in the neuronal UCPs. The results of this biophysical study can have important implications for understanding the mechanisms of function/dysfunction of mitochondria and their role in health and disease.