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bioRxiv · 10.1101/2024.02.11.579862

SLC-25A46 Regulates Mitochondrial Fusion through FZO-1/Mitofusin and is Essential for Maintaining Neuronal Morphology

Obinata, H.·Takahashi, H.·Shimo, S.·Oda, T.·Sugimoto, A.·Niwa, S.
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Abstract

Mitochondria are dynamic organelles shaped by sequential fission and fusion events. The mitochondrial protein SLC25A46 has been identified as a causative gene for mitochondrial neuropathies. However, the function of SLC25A46 in mitochondrial morphogenesis remains controversial, with several reports suggesting it acts as a mitochondrial fission factor, while others propose it as a fusion factor. In this study, employing forward genetics, we identified slc-25A46, a Caenorhabditis elegans orthologue of human SLC25A46, as an essential factor for mitochondrial fusion. Suppressor mutagenesis screening revealed loss-of-function mutations in drp-1, a mitochondrial fission factor, as suppressors of slc-25A46. The phenotype of slc-25A46 mutants is similar to those of fzo-1 mutants, wherein the mitochondrial fusion factor Mitofusin is disrupted. Overexpressing FZO-1/Mitofusin mitigated mitochondrial defects in slc-25a46 mutants, indicating SLC-25A46 promotes fusion through FZO-1/Mitofusin. Disease model worms carrying mutations associated with SLC25A46 exhibited mitochondrial fragmentation and accelerated neurodegeneration, suggesting slc-25A46 maintains neuronal morphology through mitochondrial fusion regulation.

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Obinata, H., Takahashi, H., Shimo, S., Oda, T., Sugimoto, A., Niwa, S.. 2024-02-12. SLC-25A46 Regulates Mitochondrial Fusion through FZO-1/Mitofusin and is Essential for Maintaining Neuronal Morphology. https://doi.org/10.1101/2024.02.11.579862

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