Altered axonal mitochondrial transport in the pathogenesis of Charcot-Marie-Tooth disease from mitofusin 2 mutations.
Mutations in the mitochondrial fusion protein mitofusin 2 (MFN2) are the most commonly identified cause of Charcot-Marie-Tooth type 2 (CMT2), a dominantly inherited disease characterized by degeneration of peripheral sensory and motor axons. However, the mechanism by which mutations in this ubiquitously expressed mitochondrial fusion protein lead to neuropathy has not yet been elucidated. To explore how MFN2 mutations lead to degeneration of peripheral axons, we expressed neuropathy-associated forms of MFN2 in cultured dorsal root ganglion neurons, cells preferentially affected in CMT2. Disease-associated MFN2 mutant proteins induced abnormal clustering of small fragmented mitochondria in both neuronal cell bodies and proximal axons. Interestingly, transport of mitochondria in axons was significantly impaired in neurons expressing disease-mutated forms of MFN2. The diminished axonal mitochondrial transport was not attributable to diminished ATP levels in the neurons, and oxidative respiration was normal in mutant MFN2-expressing cells. Additionally, mitochondrial oxidative enzyme activity was normal in muscle mitochondria from a CMT2 patient with an MFN2 mutation, further supporting that abnormal mitochondrial transport in neurons is independent from an energy production defect. This abnormal mitochondrial trafficking provides a likely explanation for the selective susceptibility of the longest peripheral axons to MFN2 mutations, in which proper localization of mitochondria is critical for axonal and synaptic function.
Baloh
Robert H
RH
Department of Neurology, Washington University School of Medicine, St. Louis, Missouri 63110, USA. balohb@neuro.wustl.edu
Schmidt
Robert E
RE
Pestronk
Alan
A
Milbrandt
Jeffrey
J
D000818:Animals; D001370:Axonal Transport / Q000235:genetics*; D002460:Cell Line; D002478:Cells, Cultured; D002607:Charcot-Marie-Tooth Disease / Q000235:genetics* / Q000378:metabolism* / Q000473:pathology; D005260:Female; D020558:GTP Phosphohydrolases; D006801:Humans; D008565:Membrane Proteins / Q000235:genetics* / Q000502:physiology; D008928:Mitochondria / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D024101:Mitochondrial Proteins / Q000235:genetics* / Q000502:physiology; D009154:Mutation; D011247:Pregnancy; D051381:Rats; D017207:Rats, Sprague-Dawley
D008565:Membrane Proteins; D024101:Mitochondrial Proteins; D020558:GTP Phosphohydrolases; C470018:MFN2 protein, human