VPS13D mutations affect mitochondrial homeostasis and locomotion in Caenorhabditis elegans.

Publisher: Oxford University Press Country of Publication: England NLM ID: 101566598 Publication Model: Print Cited Medium: Internet ISSN: 2160-1836 (Electronic) Linking ISSN: 21601836 NLM ISO Abbreviation: G3 (Bethesda) Subsets: MEDLINE

Publication: 2021- : [Oxford] : Oxford University Press
Original Publication: Bethesda, MD : Genetics Society of America, 2011-

Caenorhabditis elegans*/genetics ; Caenorhabditis elegans*/physiology ; Mitochondria*/metabolism ; Mitochondria*/genetics ; Caenorhabditis elegans Proteins*/genetics ; Caenorhabditis elegans Proteins*/metabolism ; Locomotion*/genetics ; Homeostasis*/genetics ; Mutation*; Animals ; Unfolded Protein Response/genetics ; CRISPR-Cas Systems ; Humans

Competing Interests: Conflicts of interest: The authors declare no conflict of interest.
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.
(© The Author(s) 2025. Published by Oxford University Press on behalf of The Genetics Society of America.)

Update of: bioRxiv. 2025 Jan 25:2025.01.22.634397. doi: 10.1101/2025.01.22.634397.. (PMID: 39896501)

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R01 GM140480 United States GM NIGMS NIH HHS; R01 AG082740 United States AG NIA NIH HHS; P40 OD010440 United States OD NIH HHS; R01 GM140480 United States NH NIH HHS; R35 GM131689 United States GM NIGMS NIH HHS

Keywords: Caenorhabditis elegans; VPS13D; vps-13D; WormBase; mitochondrial homeostasis

0 (Caenorhabditis elegans Proteins)

Date Created: 20250217 Date Completed: 20250417 Latest Revision: 20250721

20250721

PMC12005150

10.1093/g3journal/jkaf023

39957248