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

Abstract

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., Friedreichs 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.

O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=135 SRC="FIGDIR/small/26362166v1_ufig1.gif" ALT="Figure 1"> View larger version (46K): [email protected]@ec8b11org.highwire.dtl.DTLVardef@19e41fborg.highwire.dtl.DTLVardef@fdfcef_HPS_FORMAT_FIGEXP M_FIG Graphical Abstract

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BibTeX RIS

BibTeX

@misc{zaman2026characterization,
  title = {{Characterization of Ataxia-linked MFN2 Variants Reveals a Lipid Droplet/Mitochondrial Axis Driving Ferroptosis}},
  author = {M. Zaman and A. Mohan and C. Chute and F. Sousa Monteiro and A. Zardini Buzatto and T. Shutt},
  howpublished = {medRxiv},
  year = {2026},
  month = sep,
  doi = {10.64898/2026.09.19.26362166},
  url = {https://www.medrxiv.org/content/10.64898/2026.09.19.26362166v1},
  note = {CC BY-NC},
}

RIS

TY  - UNPB
TI  - Characterization of Ataxia-linked MFN2 Variants Reveals a Lipid Droplet/Mitochondrial Axis Driving Ferroptosis
AU  - M. Zaman
AU  - A. Mohan
AU  - C. Chute
AU  - F. Sousa Monteiro
AU  - A. Zardini Buzatto
AU  - T. Shutt
PY  - 2026
DA  - 2026/09/19
PB  - medRxiv
DO  - 10.64898/2026.09.19.26362166
UR  - https://www.medrxiv.org/content/10.64898/2026.09.19.26362166v1
AB  - 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., Friedreichs 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.  O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=135 SRC="FIGDIR/small/26362166v1_ufig1.gif" ALT="Figure 1"> View larger version (46K): [email protected]@ec8b11org.highwire.dtl.DTLVardef@19e41fborg.highwire.dtl.DTLVardef@fdfcef_HPS_FORMAT_FIGEXP M_FIG Graphical Abstract  C_FIG
ER  -

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