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

基本信息

批准号：
10467011
负责人：
Vishal Mahendrasingh Gohil
金额：
$ 31.18万
依托单位：
TEXAS A&M AGRILIFE RESEARCH
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 2024-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10467011
关键词：
Address Antineoplastic Agents Binding Binding Proteins Biochemical Biochemistry Bypass Cells Client Complex Copper Cysteine Disease Disulfides Energy Metabolism Environment Enzymes Genes Genetic Growth Human Hypoxia In Vitro Inherited Investigation Knowledge Mediating Menkes Kinky Hair Syndrome Micronutrients Mitochondria Mitochondrial Diseases Mitochondrial Proteins Modeling Molecular Mutate Organ Oxidases Oxidation-Reduction Oxygen Consumption PTGS1 gene PTGS2 gene Pathway interactions Patients Play Process Production Proteins Respiration Role Site Structure Sulfhydryl Compounds Testing Therapeutic Thiol Disulfide Oxidoreductase Work Yeast Model System Yeasts base cofactor cytochrome c oxidase disulfide bond effective therapy experimental study in vivo infancy loss of function mutation member novel overexpression oxidation prevent protein protein interaction public health relevance respiratory respiratory enzyme trafficking yeast genetics

项目摘要

Modified Project Summary/Abstract Section Copper (Cu) is an essential micronutrient that acts as a catalytic cofactor for a number of enzymes including cytochrome c oxidase (CcO), a critical enzyme required for mitochondrial energy production. Cu delivery to CcO is a complex process requiring multiple proteins, and loss-of-function mutations in several of the genes encoding these proteins cause fatal infantile disorders. Currently, no effective therapy exists for these fatal disorders. This is due, in part, to our incomplete understanding of how Cu is trafficked to the mitochondria and is delivered to the Cu-containing subunits of CcO. To address this gap in our knowledge, we use complementary approaches involving yeast genetics and biochemistry to discover and characterize the novel mitochondrial proteins that facilitate Cu delivery to CcO. Using these approaches, we have found the evolutionarily conserved mitochondrial proteins Coa4 and Coa6 as new members of the mitochondrial Cu delivery pathways to CcO. Now, we aim to define the biochemical functions of Coa4 and Coa6 in the Cu delivery process. Our preliminary findings, including the structure of human COA6, have led us to hypothesize that Coa4 and Coa6 play redox roles in Cu delivery to CcO. We will test this hypothesis by determining the in vitro and in vivo redox states of Coa4- and Coa6- interacting proteins and by defining the physical basis of interaction through genetic and protein:protein interaction studies. Thus, the proposed project addresses fundamental questions in Cu delivery mechanisms to CcO.

修改的项目摘要/摘要部分铜（Cu）是必不可少的微量营养素，它是包括细胞色素C氧化酶（CCO）的许多酶的催化辅因子，这是线粒体能量生产所需的关键酶。 CU向CCO递送是一个需要多种蛋白质的复杂过程，并且在编码这些蛋白质的几个基因中的功能丧失突变会引起致命的婴儿疾病。目前，这些致命疾病尚无有效的疗法。这部分归因于我们对CU如何被贩运到线粒体的不完全理解，并将其交付给CCO的含Cu亚基。为了解决这一差距，我们使用涉及酵母遗传学和生物化学的互补方法来发现和表征新型的线粒体蛋白，从而促进CU递送到CCO。使用这些方法，我们发现进化保守的线粒体蛋白CoA4和CoA6是线粒体CU递送途径的新成员。现在，我们旨在定义CU输送过程中COA4和COA6的生化功能。我们的初步发现，包括人类COA6的结构，使我们假设COA4和COA6在CU传递给CCO中扮演了氧化还原角色。我们将通过确定COA4-和COA6-相互作用蛋白的体外和体内氧化还原状态，并通过遗传和蛋白质的物理基础来检验这一假设：蛋白质相互作用研究。因此，拟议的项目解决了向CCO传递机制中的基本问题。

项目成果

期刊论文数量（19）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Specific requirements of nonbilayer phospholipids in mitochondrial respiratory chain function and formation.

DOI：
10.1091/mbc.e15-12-0865
发表时间：
2016-07-15
期刊：
Molecular biology of the cell
影响因子：
3.3
作者：
Baker CD;Basu Ball W;Pryce EN;Gohil VM
通讯作者：
Gohil VM

Repurposing elesclomol, an investigational drug for the treatment of copper metabolism disorders.

DOI：
10.1080/13543784.2021.1840550
发表时间：
2021-01
期刊：
Expert opinion on investigational drugs
影响因子：
6.1
作者：
Gohil VM
通讯作者：
Gohil VM

Choline restores respiration in Psd1-deficient yeast by replenishing mitochondrial phosphatidylethanolamine.

DOI：
10.1016/j.jbc.2021.100539
发表时间：
2021-01
期刊：
The Journal of biological chemistry
影响因子：
0
作者：
Iadarola DM;Joshi A;Caldwell CB;Gohil VM
通讯作者：
Gohil VM

FDX1 Is Required for the Biogenesis of Mitochondrial Cytochrome c Oxidase in Mammalian Cells.

FDX1 是哺乳动物细胞中线粒体细胞色素 c 氧化酶的生物发生所必需的。

DOI：
10.1016/j.jmb.2023.168317
发表时间：
2023
期刊：
Journal of molecular biology
影响因子：
5.6
作者：
Zulkifli,Mohammad;Okonkwo,AdrianaU;Gohil,VishalM
通讯作者：
Gohil,VishalM

Yeast homologs of human MCUR1 regulate mitochondrial proline metabolism.

DOI：
10.1038/s41467-020-18704-1
发表时间：
2020-09-25
期刊：
Nature communications
影响因子：
16.6
作者：
Zulkifli M;Neff JK;Timbalia SA;Garza NM;Chen Y;Watrous JD;Murgia M;Trivedi PP;Anderson SK;Tomar D;Nilsson R;Madesh M;Jain M;Gohil VM
通讯作者：
Gohil VM