Charcot–Marie–Tooth type 2A variants of mitofusin 2 sensitize cells to apoptotic cell death

The neuropathy Charcot-Marie-Tooth (CMT) is an incurable disease with a lack of genotype-phenotype correlation. Variants of the mitochondrial protein mitofusin 2 (MFN2), a large GTPase that mediates mitochondrial fusion, are responsible for the subtype CMT type 2A (CMT2A). Interestingly, beyond membrane remodelling, additional roles of MFN2 have been identified, expanding the possibilities to explore its involvement in disease. Here, we investigated how cellular functions of MFN2 are associated with variants present in individuals with CMT2A. Using human cellular models, we observed that cells expressing CMT2A variants display increased endoplasmic reticulum (ER) stress and apoptotic cell death. Increased cleavage of PARP1, caspase 9, caspase 7 and caspase 3, alongside BAX translocation to mitochondria, pointed towards effects on intrinsic apoptosis. Moreover, although disruption of fusion and fission dynamics per se did not correlate with cell death markers, expression of MFN1 or MFN2 alleviated the apoptosis markers of CMT2A variant cell lines. In sum, our results highlight excessive cell death by intrinsic apoptosis as a potential target in CMT2A disease.