VPS13C, also associated with PARK23, is a protein-coding gene. It encodes a lipid transfer protein localizing to contact sites between the ER and late endosomes/lysosomes [2,3,10]. It plays a crucial role in regulating mitochondrial function via the endolysosomal pathway in neurons, and is thus of great biological importance in neural-related processes [1].

Mutations in VPS13C cause early-onset, autosomal recessive Parkinson's disease (PD) [2,6,9]. Depleting VPS13C in HeLa cells leads to an abnormal lipid profile in lysosomes, activation of the cGAS-STING pathway due to elevated cytosolic mitochondrial DNA and defective STING degradation [2]. In human iPSC-derived dopaminergic neurons, loss of VPS13C disrupts lysosomal morphology, dynamics, motility, distribution, hydrolytic activity, and acidification, as well as the phospho-Rab10-mediated lysosomal stress response [4]. VPS13C also rapidly relocates to damaged lysosomes to tether their membranes to the ER, suggesting it's part of an early protective response to lysosome damage [5]. Additionally, downregulation of VPS13C promotes cisplatin resistance in cervical cancer by upregulating GSTP1 and inhibiting the JNK pathway [7]. Loss of either VPS13A or VPS13C in U-2 OS cells via CRISPR-Cas9 genome editing reduces lipid droplet abundance under oleate-stimulated conditions [8].

In summary, VPS13C is essential for maintaining normal lysosomal and mitochondrial functions, lipid homeostasis, and may be involved in the body's response to cell stress. Its malfunction, as revealed through loss-of-function experiments in cell lines, is closely associated with Parkinson's disease and cisplatin-resistant cervical cancer, highlighting its significance in understanding these disease mechanisms.