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Mitochondrial complex I: An intricate energy-converting machine, a cornerstone of mitochondrial metabolism, and a locus of mitochondrial dysfunction and disease

线粒体复合体 I：一种复杂的能量转换机器，线粒体代谢的基石，以及线粒体功能障碍和疾病的根源

基本信息

批准号：
MC_UU_00028/1
负责人：
Judy Hirst
金额：
$ 509.43万
依托单位：
University of Cambridge
依托单位国家：
英国
项目类别：
Intramural
财政年份：
2022
资助国家：
英国
起止时间：
2022 至无数据
项目状态：
未结题

来源：
https://gtr.ukri.org/projects?ref=MC_UU_00028%2F1
关键词：
Mitochondrial complex intricate energy converting

项目摘要

Dysfunctions of mitochondrial complex I, the first of four energy-converting complexes that power the cell to produce ATP by oxidative phosphorylation, cause many mitochondrial diseases. Following the ‘resolution revolution’ in cryo-electron microscopy (cryoEM) the structure of mammalian complex I has been solved, but many key aspects of how the enzyme works remain unknown. It is further unclear how it is regulated, repaired or replaced; how its structure, function or assembly are affected by clinically-identified mutations; or how reactive oxygen species, drugs or toxins affect its catalysis and function in the cell. Even when a mutation in a well-characterised complex I gene is established as the direct cause of a mitochondrial disease, the pathological mechanisms that define the pathways from the molecular defect to the clinical symptoms are poorly understood.The aims of the Mitochondrial Complex I programme are to define and understand the molecular structure, function and dysfunction of mammalian complex I, and to exploit and apply this basic knowledge to understand complex I in vivo, elucidate disease mechanisms, support clinical diagnoses, and contribute to the development of therapeutic strategies against both primary diseases and complex multifactorial disorders involving complex I.

线粒体复合体I是四个能量转换复合体中的第一个，通过氧化磷酸化为细胞提供能量以产生ATP，它的功能障碍会导致许多线粒体疾病。随着低温电子显微镜（cryoEM）的“分辨率革命”，哺乳动物复合体I的结构已经解决，但酶如何工作的许多关键方面仍然未知。目前还不清楚它是如何被监管、修复或替换的；临床鉴定的突变如何影响其结构、功能或组装；或者活性氧、药物或毒素如何影响其在细胞中的催化作用和功能。即使在一个特征明确的复合体I基因突变被确定为线粒体疾病的直接原因时，定义从分子缺陷到临床症状的途径的病理机制也知之甚少。线粒体复合体I项目的目标是定义和理解哺乳动物复合体I的分子结构、功能和功能障碍，并开发和应用这些基础知识来了解体内复合体I，阐明疾病机制，支持临床诊断，并为针对原发疾病和涉及复合体I的复杂多因子疾病的治疗策略的发展做出贡献。