title: Mitochondrial fusion and function in Charcot-Marie-Tooth type 2A patient fibroblasts with mitofusin 2 mutations.
abstract: Charcot-Marie-Tooth Type 2A is a dominantly inherited peripheral neuropathy characterized by axonal degeneration of sensory and motor nerves. The disease is caused by mutations in the mitochondrial fusion gene MFN2. Mfn2 is an integral outer mitochondrial membrane protein composed of a large GTPase domain and two heptad repeat (HR) domains that face the cytoplasm. Mitochondrial membrane fusion and division are balanced processes that are necessary to maintain tubular mitochondrial morphology, respiratory function, and uniform distribution of the organelle throughout the cell. We have utilized primary fibroblasts from CMT2A patients to survey mitochondrial phenotypes associated with heterozygous MFN2 alleles expressed at physiological levels. Our results indicate that, in fibroblasts, mitofusin expression, mitochondrial morphology, ultrastructure, mtDNA content, and respiratory capacity are not affected by the presence of mutant Mfn2 protein. Consistent with a lack of mitochondrial dysfunction, we also show that mitochondrial fusion occurs efficiently in CMT2A patient-derived fibroblasts. Our observations are in agreement with the neuronal specificity of the disease and are consistent with a recent finding that mitochondrial fusion can be maintained in cells that express mutant Mfn2 protein due to complementation by a second mitofusin, Mfn1. We discuss our results and those of others in terms of a comprehensive model for the mechanism(s) by which mutations in MFN2 may lead to CMT2A disease.
authors.affiliation: Department of Biochemistry, University of Utah School of Medicine, 15 N. Medical Drive East, Salt Lake City, UT 84112, USA.
authors.forename: Elizabeth A
authors.initials: EA
authors.lastname: Amiott
authors.forename: Paul
authors.initials: P
authors.lastname: Lott
authors.forename: Jamie
authors.initials: J
authors.lastname: Soto
authors.forename: Peter B
authors.initials: PB
authors.lastname: Kang
authors.forename: J Michael
authors.initials: JM
authors.lastname: McCaffery
authors.forename: Salvatore
authors.initials: S
authors.lastname: DiMauro
authors.forename: E Dale
authors.initials: ED
authors.lastname: Abel
authors.forename: Kevin M
authors.initials: KM
authors.lastname: Flanigan
authors.forename: Victoria H
authors.initials: VH
authors.lastname: Lawson
authors.forename: Janet M
authors.initials: JM
authors.lastname: Shaw
mesh_terms: D002478:Cells, Cultured; D002607:Charcot-Marie-Tooth Disease / Q000235:genetics* / Q000473:pathology*; D004252:DNA Mutational Analysis; D004272:DNA, Mitochondrial / Q000502:physiology; D005347:Fibroblasts / Q000473:pathology* / Q000502:physiology; D020558:GTP Phosphohydrolases / Q000235:genetics / Q000378:metabolism; D049452:Green Fluorescent Proteins / Q000235:genetics / Q000378:metabolism; D006801:Humans; D008565:Membrane Proteins / Q000235:genetics*; D026901:Membrane Transport Proteins / Q000235:genetics / Q000378:metabolism; D046529:Microscopy, Electron, Transmission; D008928:Mitochondria / Q000378:metabolism / Q000473:pathology* / Q000648:ultrastructure; D033681:Mitochondrial Membrane Transport Proteins; D024101:Mitochondrial Proteins / Q000235:genetics* / Q000378:metabolism; D009097:Multienzyme Complexes / Q000378:metabolism; D009154:Mutation / Q000235:genetics*; D010101:Oxygen Consumption / Q000235:genetics; D014161:Transduction, Genetic / Q000379:methods
chemical_list: D004272:DNA, Mitochondrial; D008565:Membrane Proteins; D026901:Membrane Transport Proteins; D033681:Mitochondrial Membrane Transport Proteins; D024101:Mitochondrial Proteins; D009097:Multienzyme Complexes; D049452:Green Fluorescent Proteins; D020558:GTP Phosphohydrolases; C470018:MFN2 protein, human; C470017:Mfn1 protein, human