VPS13D Mutations Affect Mitochondrial Homeostasis and Locomotion in Caenorhabditis elegans

Mitochondria control cellular metabolism, serve as hubs for signaling and organelle communication, and are important for the health and survival of cells. _VPS13D_ encodes a cytoplasmic lipid transfer protein that regulates mitochondrial morphology, mitochondria and endoplasmic reticulum (ER) contact, quality control of mitochondria. _VPS13D_ mutations have been reported in patients displaying ataxic and spastic gait disorders with variable age of onset. Here we used CRISPR/Cas9 gene editing to create _VPS13D_ related-spinocerebellar ataxia-4 (SCAR4) missense mutations and C-terminal deletion in _VPS13D_’s orthologue _vps-13D_ in _C. elegans_. Consistent with SCAR4 patient movement disorders and mitochondrial dysfunction, _vps-13D_ mutant worms exhibit locomotion defects and abnormal mitochondrial morphology. Importantly, animals with a _vps-13D_ deletion or a N3017I missense mutation exhibited an increase in mitochondrial unfolded protein response (UPRmt). The cellular and behavioral changes caused by _VPS13D_ mutations in _C. elegans_ advance the development of animal models that are needed to study SCAR4 pathogenesis.