VPS13C/PARK23 initiates lipid transfer and membrane remodeling for efficient lysosomal repair
- Oluwatobi Andrew Adeosun
- Christian Schröer
- Elisabeth Südhoff
- Fabio Bergenthal
- Katharina Sommer
- Emely Döffinger
- Britta Fiedler
- Angelika Hilderink
- Ann-Katrin Lehmann
- Lea Sophie Pohle
- Sergei M. Korneev
- Florian Fröhlich
- Kenji Maeda
- Rainer Kurre
- Michael Holtmannspötter
- Bianca M. Esch
- Joost C. M. Holthuis
2026-07-02
Perturbations in lysosome integrity are tightly linked to neurological disorders and ageing, but the underlying pathogenic mechanisms are incompletely understood. Using an unbiased proteomic approach, we here identified the bridge-like lipid transport protein VPS13C/PARK23 as a key component of a global early response pathway to lysosome damage. VPS13C readily binds lysosomes under mechanical or osmotic tension in anticipation of membrane lesions. The latter trigger a conformational change in the protein’s C -terminus, involving its ATG2C domain acting as sensor of damage-induced lipid packing defects. We show that ER-lysosome contacts formed by VPS13C provide critical binding platforms for OSBP/ORPs to enable efficient ER wrapping of damaged lysosomes. A chemical approach to assess directional ER-to-lysosome lipid transport revealed that VPS13C is essential for large-scale lipid delivery to acutely damaged lysosomes to facilitate their repair. Our findings offer new mechanistic insights into how loss-of-function mutations in VPS13C may enhance the risk of Parkinson’s disease.