Regulation of lysosomal ion homeostasis by channels and transporters

Lysosomes are the major organelles that carry out degradation functions. They integrate and digest materials compartmental- ized by endocytosis, phagocytosis or autophagy. In addition to more than 60 hydrolases residing in the lysosomes, there are also ion channels and transporters that mediate the flux or transport of H＋, Ca2＋, Na＋, K＋, and C1- across the lysosomal mem- branes. Defects in ionic exchange can lead to abnormal lysosome morphology, defective vesicle trafficking, impaired autoph- agy, and diseases such as neurodegeneration and lysosomal storage disorders. The latter are characterized by incomplete lyso- somal digestion and accumulation of toxic materials inside enlarged intracellular vacuoles. In addition to degradation, recent studies have revealed the roles of lysosomes in metabolic pathways through kinases such as mechanistic target of rapamycin （mTOR） and transcriptional regulation through calcium signaling molecules such as transcription factor EB （TFEB） and cal- cineurin. Owing to the development of new approaches including genetically encoded fluorescence probes and whole endoly- sosomal patch clamp recording techniques, studies on lysosomal ion channels have made remarkable progress in recent years. In this review, we will focus on the current knowledge of lysosome-resident ion channels and transporters, discuss their roles in maintaining lysosomal function, and evaluate how their dysfunction can result in disease.