C12ORF54 mediates lipid droplet delivery to lysosomes with mutation causing childhood-onset metabolic dysfunction-associated steatotic liver disease.

Authors

Ashish Negi, Abhishek Kumar, Yogendra Pratap Mathuria, Shailesh Kumar Gupta, Debasish Kumar Ghosh

Published in

Biochimica et biophysica acta. Molecular basis of disease. Volume 1873. Issue 1. Pages 168453. Sep 05, 2026. Epub Sep 05, 2026.

Abstract

Cellular lipid droplet (LD) turnover is essential for metabolic homeostasis in liver, and failures in LD clearance are increasingly linked to fatty liver disease. We describe a previously unrecognized mechanism of LD turnover and a human disorder caused by its disruption. A 2-year-old boy with metabolic dysfunction-associated steatotic liver disease (MASLD) was found by exome sequencing to carry an ultrarare homozygous C12ORF54 missense variant (c.134A>G; p.Q45R). We find that wild-type C12ORF54 is a conserved protein that binds LDs via a central amphipathic helix and tethers to lysosomes through an N-terminal helix interaction with the BORC subunit KXD1, enabling direct deposition of LDs into lysosomes. The p.Q45R substitution sterically destabilizes the amphipathic helix, abolishes KXD1 binding, prevents LD and lysosome targeting and blocks LD deposition. Proband cells accumulate LDs and acyl lipid species, lipotoxic stress due to excess ROS, and exhibit cell-cycle arrest and cell death. This study implicates defective direct lysosomal LD deposition as a cause of childhood-onset MASLD-like hepatic phenotype, and finds the C12ORF54-KXD1 interaction axis as a potential contributor to LD homeostasis in liver.

PMID:
42700646
Bibliographic data and abstract were imported from PubMed on 06 Sep 2026.

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