title: A mutation associated with CMT2A neuropathy causes defects in Fzo1 GTP hydrolysis, ubiquitylation, and protein turnover.
abstract: 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.
authors.affiliation: Department of Biochemistry, University of Utah School of Medicine, Salt Lake City, UT 84112, USA.
authors.forename: Elizabeth A
authors.initials: EA
authors.lastname: Amiott
authors.forename: Mickael M
authors.initials: MM
authors.lastname: Cohen
authors.forename: Yann
authors.initials: Y
authors.lastname: Saint-Georges
authors.forename: Allan M
authors.initials: AM
authors.lastname: Weissman
authors.forename: Janet M
authors.initials: JM
authors.lastname: Shaw
mesh_terms: D000595:Amino Acid Sequence; D019069:Cell Respiration / Q000502:physiology; D002607:Charcot-Marie-Tooth Disease / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology; D020558:GTP Phosphohydrolases / Q000235:genetics / Q000378:metabolism*; D006160:Guanosine Triphosphate / Q000378:metabolism*; D006801:Humans; D008561:Membrane Fusion / Q000502:physiology; D008565:Membrane Proteins / Q000235:genetics* / Q000378:metabolism*; D008928:Mitochondria / Q000378:metabolism / Q000648:ultrastructure; D024101:Mitochondrial Proteins / Q000235:genetics* / Q000378:metabolism*; D008969:Molecular Sequence Data; D009154:Mutation; D010641:Phenotype; D029701:Saccharomyces cerevisiae Proteins / Q000235:genetics / Q000378:metabolism*; D054875:Ubiquitination
chemical_list: D008565:Membrane Proteins; D024101:Mitochondrial Proteins; D029701:Saccharomyces cerevisiae Proteins; D006160:Guanosine Triphosphate; C401395:FZO1 protein, S cerevisiae; D020558:GTP Phosphohydrolases; C470018:MFN2 protein, human