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Determining the mechanism of mitochondrial outer membrane fusion

确定线粒体外膜融合的机制

基本信息

批准号：
10807828
负责人：
Suzanne C Hoppins
金额：
$ 1.62万
依托单位：
UNIVERSITY OF WASHINGTON
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-02-01 至 2026-04-30
项目状态：
未结题

项目摘要

Project Summary This proposal examines the mitofusin proteins, which catalyze both mitochondrial tethering and outer membrane fusion. Mitochondrial shape is central to mitochondrial function and is closely linked to changes in cellular physiology during development, stress, and aging. Mitochondrial fusion increases metabolic production, protects against excessive degradation of mitochondria, reduces sensitivity of the cell to apoptotic stimuli and allows functional complementation of damaged organelles. Compromised mitochondrial function and decreased organelle connectivity are associated with neurodegeneration and other age-related diseases. Furthermore, mutations in the genes encoding components of the mitochondrial fusion machine cause peripheral neuropathy, optic atrophy, myopathy and ataxia. Both mitochondrial division and mitochondrial fusion are mediated by conserved dynamin superfamily proteins. This diverse family of mechanochemical GTPases couple self-assembly and conformational changes to membrane remodeling events throughout the cell. Mitofusin is the mitochondrial outer membrane fusion machine and must assemble both in cis within a single membrane, and in trans across two mitochondria. The molecular details, including of the composition of these assemblies, the regulation of their formation and how they contribute to membrane tethering and fusion are not known. We address these gaps in knowledge utilizing biochemical analyses of mitofusin function. In Aim 1, we will elucidate mechanisms of allosteric regulation that control assembly of mitofusin into fusion- competent complexes. Our collection of functional variants and novel approaches will provide a powerful tool in dissecting the contribution of each mitofusin functional domain to cis oligomerization and trans complex formation. Our work characterizing CMT2A-associated variants of mitofusin revealed that molecular defects of mitofusin can be compensated for by cytosolic factors in cells. In Aim 2, we use a reductionist approach that combines cell biology, biochemistry, and reconstituted assays developed in my lab to determine how the cytosolic mitofusin effector Bax alters mitofusin assembly to regulate mitochondrial fusion. This research program draws on our strengths in cellular and biochemical analysis of mitochondrial biology and will yield fundamental insights not only for mitochondrial dynamics but for the mechanisms through which dynamin superfamily proteins in general operate.

项目总结

项目成果

期刊论文数量（8）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

A dominant negative mitofusin causes mitochondrial perinuclear clusters because of aberrant tethering.

DOI：
10.26508/lsa.202101305
发表时间：
2023-01
期刊：
LIFE SCIENCE ALLIANCE
影响因子：
4.4
作者：
Sloat, Stephanie R.;Hoppins, Suzanne
通讯作者：
Hoppins, Suzanne

In vitro and in vivo assays for mitochondrial fission and fusion.

线粒体裂变和融合的体外和体内测定。

DOI：
10.1016/bs.mcb.2019.11.010
发表时间：
2020
期刊：
Methods in cell biology
影响因子：
0
作者：
Hoppins S;Lackner LL;Lee JE;Mears JA
通讯作者：
Mears JA

Cell-Free Analysis of Mitochondrial Fusion by Fluorescence Microscopy.

通过荧光显微镜对线粒体融合的无细胞分析。

DOI：
10.1007/978-1-0716-0676-6_10
发表时间：
2020
期刊：
Methods in molecular biology (Clifton, N.J.)
影响因子：
0
作者：
Samanas NB;Hoppins S
通讯作者：
Hoppins S

Full-length isoform sequencing for resolving the molecular basis of Charcot-Marie-Tooth 2A.

用于解析 Charcot-Marie-Tooth 2A 分子基础的全长异构体测序。

DOI：
10.1101/2023.02.07.526487
发表时间：
2023
期刊：
bioRxiv : the preprint server for biology
影响因子：
0
作者：
Stergachis,AndrewB;Blue,ElizabethE;Gillentine,MadelynA;Wang,Lee-Kai;Schwarze,Ulrike;Cortés,AdrianaSedeño;Ranchalis,Jane;Allworth,Aimee;Bland,AustinE;Chanprasert,Sirisak;Chen,Jingheng;Doherty,Daniel;Folta,AndrewB;Glass,Ian;
通讯作者：