title: Mitochondrial fusion protects against neurodegeneration in the cerebellum.
abstract: Mutations in the mitochondrial fusion gene Mfn2 cause the human neurodegenerative disease Charcot-Marie-Tooth type 2A. However, the cellular basis underlying this relationship is poorly understood. By removing Mfn2 from the cerebellum, we established a model for neurodegeneration caused by loss of mitochondrial fusion. During development and after maturity, Purkinje cells require Mfn2 but not Mfn1 for dendritic outgrowth, spine formation, and cell survival. In vivo, cell culture, and electron microscopy studies indicate that mutant Purkinje cells have aberrant mitochondrial distribution, ultrastructure, and electron transport chain activity. In fibroblasts lacking mitochondrial fusion, the majority of mitochondria lack mitochondrial DNA nucleoids. This deficiency provides a molecular mechanism for the dependence of respiratory activity on mitochondrial fusion. Our results show that exchange of mitochondrial contents is important for mitochondrial function as well as organelle distribution in neurons and have important implications for understanding the mechanisms of neurodegeneration due to perturbations in mitochondrial fusion.
authors: Division of Biology, California Institute of Technology, Pasadena, CA 91125, USA.
authors: Hsiuchen
authors: H
authors: Chen
authors: J Michael
authors: JM
authors: McCaffery
authors: David C
authors: DC
authors: Chan
mesh_terms: D000818:Animals; D002531:Cerebellum / Q000201:enzymology* / Q000473:pathology / Q000648:ultrastructure; D020558:GTP Phosphohydrolases / Q000235:genetics*; D007425:Intracellular Membranes / Q000201:enzymology / Q000502:physiology; D008561:Membrane Fusion / Q000235:genetics*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008928:Mitochondria / Q000235:genetics* / Q000648:ultrastructure; D019636:Neurodegenerative Diseases / Q000235:genetics / Q000473:pathology / Q000517:prevention & control*; D011689:Purkinje Cells / Q000201:enzymology / Q000473:pathology
chemical_list: D020558:GTP Phosphohydrolases; C488750:Mfn1 protein, mouse; C488751:Mfn2 protein, mouse