Characterization of Ataxia-linked MFN2 Variants Reveals a Lipid Droplet/Mitochondrial Axis Driving Ferroptosis

Pathogenic variants in the mitochondrial protein Mitofusin 2 have long been recognized to cause the peripheral neuropathy Charcot-Marie-Tooth Type 2A (CMT2A). However, a small subset of MFN2 variants also impact the central nervous system and cause cerebellar ataxia. The reason for this discrepancy and the mechanisms underlying ataxia are unknown. Here we find a novel correlation between MFN2 variants linked to ataxia and increased susceptibility to ferroptosis. Mechanistically, we find that ataxia-linked MFN2 variants confer a gain-of-function that increases fatty acid import from lipid droplets into mitochondria, reshaping the cellular lipidome. This lipid redistribution primes cells for lipid peroxidation, ultimately increasing their susceptibility to ferroptotic cell death. Given that ferroptosis is linked to other ataxias (e.g., Friedreich's ataxia), we propose that the increased sensitivity to ferroptosis within these MFN2 ataxia variants likely explains this specific phenotype. Thus, our findings uncover a gain-of-function for MFN2 ataxia variants that cause ferroptosis and likely contributes to cerebellar ataxia through a mechanism distinct from MFN2-mediated peripheral neuropathy.