ABSTRACT
Members of mammalian mucolipin transient receptor potential (TRPML) cation channels, TRPML1-3 or MCOLN1-3, are localized predominantly on the membranes of late endosomes and lysosomes (LELs) to mediate phosphoinositide-regulated release of Ca2+ and heavy metal Fe2+/Zn2+ ions from the LEL lumen. Studies using genetic models and mammalian cell lines have revealed a broad spectrum of cellular functions for TRPMLs. ese include the maintenance of LEL ion homeostasis and the regulation of membrane tracking (fusion and ssion) in the late endocytic pathways: autophagy, LEL-toGolgi retrograde tracking, and lysosomal exocytosis. At the whole-organism level, while loss-of-function mutations in human TRPML1 cause mucolipidosis type IV (ML4), a childhood neurodegenerative lysosomal storage disease (LSD), gain-offunction mutations in mouse TPRML3 result in the varitintwaddler (Va) phenotype with hearing and pigmentation defects. In this chapter, we will discuss the current understanding
of TRPMLs regarding their tissue distribution, subcellular localization, channel properties, cellular functions, lysosome physiology, and disease relevance.
