BK Channels Alleviate Lysosomal Storage Diseases by Providing Positive Feedback Regulation of Lysosomal Ca²⁺ Release

Promoting lysosomal trafficking represents a promising therapeutic approach for lysosome storage diseases. Efficient Ca²⁺ mobilization from lysosomes is important for lysosomal trafficking. Ca²⁺ release from lysosomes could generate a negative potential in the lumen to disturb subsequent Ca²⁺ release in the absence of counter ion flux. Here we report that lysosomes express big-conductance Ca²⁺-activated potassium (BK) channels that form physical and functional coupling with the lysosomal Ca²⁺ release channel, TRPML1. Ca²⁺ release via TRPML1 causes BK activation, which in turn facilitates further lysosomal Ca²⁺ release and membrane trafficking. Importantly, BK overexpression rescues the impaired TRPML1-mediated Ca²⁺ release and abnormal lysosomal storage in cells from Niemann-Pick C1 patients. Therefore, we have identified alysosomal K⁺ channel that provides a positive feedback mechanism to facilitate TRPML1-mediated Ca²⁺ release and membrane trafficking. Our findings suggest that upregulating BK may be a potential therapeutic strategy for certain lysosomal storage diseases and common neurodegenerative disorders.