A Mutation Associated with CMT2A Neuropathy Causes Defects in Fzo1 GTP Hydrolysis, Ubiquitylation, and Protein Turnover

被引:32
作者
Amiott, Elizabeth A. [1 ]
Cohen, Mickael M. [2 ]
Saint-Georges, Yann [3 ]
Weissman, Allan M. [2 ]
Shaw, Janet M. [1 ]
机构
[1] Univ Utah, Sch Med, Dept Biochem, Salt Lake City, UT 84112 USA
[2] NCI, Lab Prot Dynam & Signaling, Frederick, MD 21702 USA
[3] Univ Paris 11, Inst Genet & Microbiol, F-91405 Orsay, France
基金
美国国家卫生研究院;
关键词
MARIE-TOOTH-DISEASE; REGULATES MITOCHONDRIAL MORPHOLOGY; CLASS-V-MYOSIN; MAMMALIAN HOMOLOGS; MITOFUSIN-2; MFN2; FUSION; YEAST; COMPLEMENTATION; MAINTENANCE; TRANSPORT;
D O I
10.1091/mbc.E09-07-0622
中图分类号
Q2 [细胞生物学];
学科分类号
071009 ; 090102 ;
摘要
Charcot-Marie-Tooth disease type 2A (CMT2A) is caused by mutations in the gene MFN2 and is one of the most common inherited peripheral neuropathies. Mfn2 is one of two mammalian mitofusin GTPases that promote mitochondrial fusion and maintain organelle integrity. It is not known how mitofusin mutations cause axonal degeneration and CMT2A disease. We used the conserved yeast mitofusin FZO1 to study the molecular consequences of CMT2A mutations on Fzo1 function in vivo and in vitro. One mutation (analogous to the CMT2A I213T substitution in the GTPase domain of Mfn2) not only abolishes GTP hydrolysis and mitochondrial membrane fusion but also reduces Mdm30-mediated ubiquitylation and degradation of the mutant protein. Importantly, complexes of wild type and the mutant Fzo1 protein are GTPase active and restore ubiquitylation and degradation of the latter. These studies identify diverse and unexpected effects of CMT2A mutations, including a possible role for mitofusin ubiquitylation and degradation in CMT2A pathogenesis, and provide evidence for a novel link between Fzo1 GTP hydrolysis, ubiquitylation, and mitochondrial fusion.
引用
收藏
页码:5026 / 5035
页数:10
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