Mitochondrial fusion and function in Charcot–Marie–Tooth type 2A patient fibroblasts with mitofusin 2 mutations

• Published in: Experimental neurology 2008-05, Vol.211 (1), p.115-127
• Main Authors: Amiott, Elizabeth A., Lott, Paul, Soto, Jamie, Kang, Peter B., McCaffery, J. Michael, DiMauro, Salvatore, Abel, E. Dale, Flanigan, Kevin M., Lawson, Victoria H., Shaw, Janet M.
• Format: Article
• Language: English
• Subjects: Biological and medical sciences; Cells, Cultured; Charcot-Marie-Tooth Disease - genetics; Charcot-Marie-Tooth Disease - pathology; CMT2A; DNA Mutational Analysis; DNA, Mitochondrial - physiology; Fibroblasts; Fibroblasts - pathology; Fibroblasts - physiology; Green Fluorescent Proteins - genetics; Green Fluorescent Proteins - metabolism; GTP Phosphohydrolases - genetics; GTP Phosphohydrolases - metabolism; GTPase; Humans; Medical sciences; Membrane fusion; Membrane Proteins - genetics; Membrane Transport Proteins - genetics; Membrane Transport Proteins - metabolism; Mfn1; Mfn2; Microscopy, Electron, Transmission; Mitochondria; Mitochondria - metabolism; Mitochondria - pathology; Mitochondria - ultrastructure; Mitochondrial Membrane Transport Proteins; Mitochondrial Proteins - genetics; Mitochondrial Proteins - metabolism; Mitofusin; Multienzyme Complexes - metabolism; Multiple sclerosis and variants. Guillain barré syndrome and other inflammatory polyneuropathies. Leukoencephalitis; Mutation - genetics; Neurology; Oxygen Consumption - genetics; Peripheral neuropathy; Transduction, Genetic - methods
• ISSN: 0014-4886; 1090-2430
• DOI: 10.1016/j.expneurol.2008.01.010

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.