A Genomic and Biochemical Analysis of Mitochondrial Respiratory Chain Biogenesis

线粒体呼吸链生物发生的基因组和生化分析

基本信息

  • 批准号:
    9033123
  • 负责人:
  • 金额:
    $ 27.39万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2014
  • 资助国家:
    美国
  • 起止时间:
    2014-08-01 至 2019-03-31
  • 项目状态:
    已结题

项目摘要

DESCRIPTION (provided by applicant): Despite the fundamental roles of the mitochondrial respiratory chain (MRC) in both cellular energy production and a number of cardiovascular, neurodegenerative and inherited metabolic disorders, many factors required for MRC formation are currently unknown. In fact, almost 20% of the approximately 1000 known human mitochondrial proteins remain completely uncharacterized. Here we propose to address the gap in our understanding of MRC formation by systematically identifying and characterizing novel MRC biogenesis factors. We have developed an integrative genomic strategy based on clues from evolutionary history, high- throughput gene expression and protein interaction studies to discover novel MRC genes. Experimental work on two of our prioritized genes, C1orf31 and C6orf57, has shown their requirement for MRC complex IV and II biogenesis, respectively. Remarkably, a recent sequencing study identified mutations in C1orf31 in a mitochondrial disease patient. Due to the immediate relevance of C1orf31 to human health, we focused on characterizing the function of this protein in a yeast model where we demonstrated that copper supplementation rescued mitochondrial respiratory defects. In the current proposal we aim to: (1) Determine the role of C1orf31 in MRC complex IV assembly; (2) Investigate the pathological consequences of the loss of C1orf31 at the mitochondrial, cellular, and organismal level and determine the pathogenicity of patient mutations; and (3) Identify additional MRC biogenesis factors using our novel RNAi-based "nutrient-sensitized" assay that utilizes differential growth of respiratory deficient human cells in glucose or galactose to interrogate mitochondrial respiration. We will perform in vitro biochemical experiments on purified C1orf31 and in vivo yeast genetic experiments to define the precise function of C1orf31 in MRC complex IV assembly. We will exploit our C1orf31 knockdown models in human cell lines and zebrafish embryos to simultaneously unravel the pathological consequences of lack of C1orf31 in mitochondrial, cellular, and organismal physiology, as well as test the hypothesis that these defects could be cured by copper supplementation. Finally, we will experimentally test our computationally predicted MRC biogenesis gene candidates, including C6orf57, for their role in cellular respiration using our nutrient-sensitized assay and assign hits to specific steps in the MRC biogenesis pathway. Thus, the impact of our work is both fundamental (elucidating basic mechanisms of MRC formation) and medical (providing the basis for molecular diagnosis of orphan mitochondrial disorders and a possible therapeutic option for patients with C1orf31 mutations).
描述(申请人提供):尽管线粒体呼吸链(MRC)在细胞能量产生和一些心血管、神经退行性和遗传性代谢紊乱中起着基本作用,但形成MRC所需的许多因素目前尚不清楚。事实上,在大约1000个已知的人类线粒体蛋白质中,几乎有20%仍然完全没有特征。在这里,我们建议通过系统地识别和表征新的MRC生物发生因素来解决我们对MRC形成的理解上的差距。我们开发了一种基于进化史、高通量基因表达和蛋白质相互作用研究的线索的综合基因组策略,以发现新的MRC基因。对我们优先考虑的两个基因C1orf31和C6orf57的实验工作表明,它们分别需要MRC复合体IV和II的生物发生。值得注意的是,最近的一项测序研究在一名线粒体疾病患者中发现了C1orf31的突变。由于C1orf31与人类健康直接相关,我们专注于在酵母模型中表征该蛋白的功能,在该模型中,我们证明了补铜可以挽救线粒体呼吸缺陷。在目前的提案中,我们的目标是:(1)确定C1orf31在MRC复合体IV组装中的作用;(2)在线粒体、细胞和组织水平上调查C1orf31丢失的病理后果,并确定患者突变的致病性;以及(3)使用我们基于RNAi的新的利用MRC复合体的差异生长来识别其他MRC生物发生因素。 葡萄糖或半乳糖中的呼吸缺陷的人类细胞,以询问线粒体的呼吸。 我们将对纯化的C1orf31进行体外生化实验和体内酵母遗传学实验,以确定C1orf31在MRC复合体IV组装中的确切功能。我们将利用我们在人类细胞系和斑马鱼胚胎中的C1orf31基因敲除模型来同时揭示线粒体、细胞和生物生理学中缺乏C1orf31的病理后果,并测试这些缺陷可以通过补充铜来治愈的假设。最后,我们将使用我们的营养敏化分析来实验测试我们计算预测的MRC生物发生基因候选基因,包括C6orf57,以确定它们在细胞呼吸中的作用,并对MRC生物发生途径中的特定步骤进行命中。因此,我们的工作的影响既是基础的(阐明MRC形成的基本机制),也是医学的(为孤儿线粒体疾病的分子诊断和C1orf31突变患者的可能治疗选择提供了基础)。

项目成果

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Vishal Mahendrasingh Gohil其他文献

Vishal Mahendrasingh Gohil的其他文献

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{{ truncateString('Vishal Mahendrasingh Gohil', 18)}}的其他基金

Mechanisms of elesclomol-mediated copper delivery to cuproenzymes in cells
来氯醇介导的铜向细胞内铜酶的传递机制
  • 批准号:
    10468271
  • 财政年份:
    2021
  • 资助金额:
    $ 27.39万
  • 项目类别:
Mechanisms of elesclomol-mediated copper delivery to cuproenzymes in cells
来氯醇介导的铜向细胞内铜酶的传递机制
  • 批准号:
    10280110
  • 财政年份:
    2021
  • 资助金额:
    $ 27.39万
  • 项目类别:
Mechanisms of elesclomol-mediated copper delivery to cuproenzymes in cells
来氯醇介导的铜向细胞内铜酶的传递机制
  • 批准号:
    10640244
  • 财政年份:
    2021
  • 资助金额:
    $ 27.39万
  • 项目类别:
Mechanisms of elesclomol-mediated copper delivery to cuproenzymes in cells
来氯醇介导的铜向细胞内铜酶的传递机制
  • 批准号:
    10580489
  • 财政年份:
    2021
  • 资助金额:
    $ 27.39万
  • 项目类别:
Molecular Mechanisms of Copper Delivery to Mitochondrial Cytochrome c Oxidase
铜传递至线粒体细胞色素 c 氧化酶的分子机制
  • 批准号:
    10250356
  • 财政年份:
    2014
  • 资助金额:
    $ 27.39万
  • 项目类别:
A Genomic and Biochemical Analysis of Mitochondrial Respiratory Chain Biogenesis
线粒体呼吸链生物发生的基因组和生化分析
  • 批准号:
    8895365
  • 财政年份:
    2014
  • 资助金额:
    $ 27.39万
  • 项目类别:
Molecular Mechanisms of Copper Delivery to Mitochondrial Cytochrome c Oxidase
铜传递至线粒体细胞色素 c 氧化酶的分子机制
  • 批准号:
    10044168
  • 财政年份:
    2014
  • 资助金额:
    $ 27.39万
  • 项目类别:
Molecular Mechanisms of Copper Delivery to Mitochondrial Cytochrome c Oxidase
铜传递至线粒体细胞色素 c 氧化酶的分子机制
  • 批准号:
    10467011
  • 财政年份:
    2014
  • 资助金额:
    $ 27.39万
  • 项目类别:
A Genomic and Biochemical Analysis of Mitochondrial Respiratory Chain Biogenesis
线粒体呼吸链生物发生的基因组和生化分析
  • 批准号:
    8757173
  • 财政年份:
    2014
  • 资助金额:
    $ 27.39万
  • 项目类别:

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