QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

Vol. 20, Issue 23, 5026-5035, December 1, 2009

This Article Full Text Full Text (PDF) Supplemental Materials All Versions of this Article: E09-07-0622v1 20/23/5026    most recent Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Amiott, E. A. Articles by Shaw, J. M. Search for Related Content PubMed PubMed Citation Articles by Amiott, E. A. Articles by Shaw, J. M.

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

Elizabeth A. Amiott^*, Mickael M. Cohen, Yann Saint-Georges, Allan M. Weissman, and Janet M. Shaw^*

*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; and Institut de Génétique et Microbiologie, Université Paris-sud, 91405 Orsay Cedex, France

Submitted July 27, 2009; Revised September 24, 2009; Accepted September 28, 2009
Monitoring Editor: Thomas D. Fox

InCytes from MBC

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.

Address correspondence to: Janet M. Shaw (shaw{at}biochem.utah.edu).

Abbreviations used: CMT2A, Charcot-Marie Tooth Disease type 2A; coIP, coimmunoprecipitation; FZO1, yeast fuzzy onions gene; GDP, guanosine diphosphate; GTP, guanosine triphosphate; HA, hemagglutinin; HR, heptad repeat; IP, immunoprecipitation; MEF, mouse embryonic fibroblast; MFN1, mitofusin 1 gene; MFN2, mitofusin 2 gene; mito-GFP, mitochondrial matrix-targeted green fluorescent protein; mito-RFP, mitochondrial matrix-targeted red fluorescent protein; TEM, transmission electron microscopy.