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

Abstract

AbstractMitochondria 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 identifiedslc-25A46, aCaenorhabditis elegansorthologue of human SLC25A46, as an essential factor for mitochondrial fusion. Suppressor mutagenesis screening revealed loss-of-function mutations indrp-1, a mitochondrial fission factor, as suppressors ofslc-25A46. The phenotype ofslc-25A46mutants is similar to those offzo-1mutants, wherein the mitochondrial fusion factor Mitofusin is disrupted. Overexpressing FZO-1/Mitofusin mitigated mitochondrial defects inslc-25a46mutants, indicating SLC-25A46 promotes fusion through FZO-1/Mitofusin. Disease model worms carrying mutations associated with SLC25A46 exhibited mitochondrial fragmentation and accelerated neurodegeneration, suggestingslc-25A46maintains neuronal morphology through mitochondrial fusion regulation.