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VPS13C/PARK23 initiates lipid transfer and membrane remodeling for efficient lysosomal repair

ABSTRACT: Perturbations in lysosome integrity are frequently 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.

INSTRUMENT(S):

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Cell Culture

SUBMITTER: Bianca Esch

LAB HEAD: Florian Fröhlich

PROVIDER: PXD069825 | Pride | 2026-07-13

REPOSITORIES: Pride

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			Action	DRS
	Lamp1_wLLOMeRep1_926.d.zip	Other
	Lamp1_wLLOMeRep2_927.d.zip	Other
	Lamp1_wLLOMeRep3_928.d.zip	Other
	Lamp1_woLLOMeRep1_923.d.zip	Other
	Lamp1_woLLOMeRep2_921.d.zip	Other

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Project description: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. This study contains shotgun lipidomics data from HeLa cells treated with L-leucyl-L-leucine methyl ester (LLOMe), a lysosomotropic agent that induces lysosomal membrane damage. Lipid profiles were obtained from both whole-cell lysates and isolated lysosomal fractions. Lipids were extracted and quantified by mass spectrometry-based shotgun lipidomics.

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