Molecular Aspects of Uncoupling Proteins

解偶联蛋白质的分子方面

• 批准号: RGPIN-2019-05900
• 负责人: JelokhaniNiaraki, Masoud
• 金额: $ 2.33万
• 依托单位: Wilfrid Laurier University
• 依托单位国家: 加拿大
• 项目类别: Discovery Grants Program - Individual
• 财政年份: 2019
• 资助国家: 加拿大
• 起止时间: 2019-01-01 至 2020-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=684344
• 关键词: Molecular; Aspects; Uncoupling; Proteins

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.

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计划的重点。迄今为止，在哺乳动物组织中已发现5种UCPs，其中3种（神经元UCPs 2、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中，作为抗氧化剂，通过将电子传递过程与ATP合成解偶联来破坏线粒体呼吸。线粒体是ATP的主要生产者，ATP是维持生命的细胞能量来源。特别地，线粒体也是过量活性氧（ROS）的重要来源，其对线粒体和细胞都有害。受损的功能失调的线粒体被认为是脑组织神经变性、创伤后死亡和衰老的主要原因之一。它已被广泛认为，UCPs可以通过其解偶联功能减少ROS的产生。除了UCP在响应氧化应激中的抗氧化作用外，还表明它们参与癌症、2型糖尿病、炎症过程和抗肥胖机制的激活。尽管这些建议显着的生理作用，除了原型UCP 1（广泛存在于棕色脂肪组织）在调节体温在年轻的哺乳动物中的既定作用，有限的信息是已知的其他哺乳动物UCPs的生物功能的结构和机制的细节。因此，一个全面的分子研究是必要的，以解开一些悬而未决的问题，不同的生理作用的UCPs在不同的组织。拟议的研究计划将是一个现有的完善的研究计划在我的实验室的延续，并将集中在：（i）线粒体模型膜的神经元解偶联蛋白的结构和分子相互作用;（ii）质子和阴离子转运的神经元UCPs的机制;和（iii）神经元UCPs在中枢神经系统的氧化应激和神经保护的调节作用。拟议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。这项生物物理学研究的结果可能对理解线粒体功能/功能障碍的机制及其在健康和疾病中的作用具有重要意义。