Résumé
Mutations in the MFN2 gene Q:9 encoding Mitofusin 2 lead to the development of Charcot-Marie-Tooth type 2A (CMT2A), a dominant axonal form of peripheral neuropathy. Mitofusin 2 is localized at both the outer membrane of mitochondria and the endoplasmic reticulum and is particularly enriched at specialized contact regions known as mitochondria-associated membranes (MAM). We observed that expression of MFN2 R94Q induces distal axonal degeneration in the absence of overt neuronal death. The presence of mutant protein leads to reduction in endoplasmic re-ticulum and mitochondria contacts in CMT2A patient-derived fi-broblasts, in primary neurons and in vivo, in motoneurons of a mouse model of CMT2A. These changes are concomitant with en-doplasmic reticulum stress, calcium handling defects, and changes in the geometry and axonal transport of mitochondria. Importantly , pharmacological treatments reinforcing endoplasmic retic-ulum-mitochondria cross-talk, or reducing endoplasmic reticulum stress, restore the mitochondria morphology and prevent axonal degeneration. These results Q:10 highlight defects in MAM as a cellular mechanism contributing to CMT2A pathology mediated by mutated MFN2.