A Ubiquitylation, and Protein Mutation Associated with CMT2A Neuropathy Causes

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Mol Biol Cell. 2009 Oct 7. [Epub ahead of print]

A Ubiquitylation, and Protein Mutation Associated with CMT2A Neuropathy Causes

Defects in Fzo1 GTP Hydrolysis, Turnover.

Amiott EA, Cohen MM, Saint-s Y, Weissman AM, Shaw JM.

Department of Biochemistry, University of Utah School of Medicine, Salt Lake

City, UT 84112; Laboratory of Protein Dynamics and Signaling, National Cancer

Institute, Frederick, MD 21702; Institut de Génétique et Microbiologie,

Université Paris-sud, 91405 Orsay Cedex, France.

Monitoring Editor: D. Fox

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, it also reduces

Mdm30-mediated ubiquitylation and degradation of the mutant protein.

Importantly, complexes of WT 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.