VPS13D mutations affect mitochondrial homeostasis and locomotion in Caenorhabditis elegans

TL;DR

This study shows that VPS13D mutations in worms cause mitochondrial issues and movement problems, similar to those seen in human patients with a related ataxia disorder.

Contribution

The study introduces a C. elegans model with VPS13D mutations to study SCAR4 pathogenesis and mitochondrial dysfunction.

Findings

vps-13D mutant worms show locomotion defects and abnormal mitochondrial morphology.

Mutations in vps-13D lead to increased mitochondrial unfolded protein response.

The model helps understand the cellular and behavioral effects of VPS13D mutations.

Abstract

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 contact, and 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 missense mutations and C-terminal deletion in VPS13D's ortholog vps-13D in Caenorhabditis 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. 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.

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