title: Complementation between mouse Mfn1 and Mfn2 protects mitochondrial fusion defects caused by CMT2A disease mutations.
abstract: Mfn2, an oligomeric mitochondrial protein important for mitochondrial fusion, is mutated in Charcot-Marie-Tooth disease (CMT) type 2A, a peripheral neuropathy characterized by axonal degeneration. In addition to homooligomeric complexes, Mfn2 also associates with Mfn1, but the functional significance of such heterooligomeric complexes is unknown. Also unknown is why Mfn2 mutations in CMT2A lead to cell type-specific defects given the widespread expression of Mfn2. In this study, we show that homooligomeric complexes formed by many Mfn2 disease mutants are nonfunctional for mitochondrial fusion. However, wild-type Mfn1 complements mutant Mfn2 through the formation of heterooligomeric complexes, including complexes that form in trans between mitochondria. Wild-type Mfn2 cannot complement the disease alleles. Our results highlight the functional importance of Mfn1-Mfn2 heterooligomeric complexes and the close interplay between the two mitofusins in the control of mitochondrial fusion. Furthermore, they suggest that tissues with low Mfn1 expression are vulnerable in CMT2A and that methods to increase Mfn1 expression in the peripheral nervous system would benefit CMT2A patients.
authors.affiliation: Division of Biology, California Institute of Technology, Pasadena, CA 91125, USA.
authors.forename: Scott A
authors.initials: SA
authors.lastname: Detmer
authors.forename: David C
authors.initials: DC
authors.lastname: Chan
mesh_terms: D000818:Animals; D001369:Axons / Q000378:metabolism / Q000473:pathology; D002478:Cells, Cultured; D002607:Charcot-Marie-Tooth Disease / Q000235:genetics* / Q000378:metabolism / Q000503:physiopathology; D005347:Fibroblasts; D020558:GTP Phosphohydrolases / Q000235:genetics* / Q000378:metabolism; D020022:Genetic Predisposition to Disease / Q000235:genetics; D046911:Macromolecular Substances / Q000378:metabolism; D008561:Membrane Fusion / Q000235:genetics*; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D008928:Mitochondria / Q000235:genetics* / Q000378:metabolism; D009154:Mutation / Q000235:genetics*; D010525:Peripheral Nerves / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D014855:Wallerian Degeneration / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology
chemical_list: D046911:Macromolecular Substances; D020558:GTP Phosphohydrolases; C488750:Mfn1 protein, mouse; C488751:Mfn2 protein, mouse