Significance
This study interrogated the roles of MFN2 catalytic activity and allosteric activation on impaired mitochondrial fusion and neuronal transport as they impact an untreatable peripheral neuropathy caused by MFN2 mutations, Charcot-Marie-Tooth disease type 2A. The results mechanistically link mitochondrial fusion and motility to the relaxed MFN2 protein conformation and correction of mitochondrial abnormalities to in vivo reversal of neurodegeneration in murine CMT2A.