TRPML1

TRPML1 (MCOLN1) is a late endosome-lysosome nonselective cation channel that releases Ca²⁺, Zn²⁺, and Fe²⁺ to regulate endocytosis, exocytosis, lysosomal biogenesis, lysosome reformation, and autophagy^[1]. Mechanistically, TRPML1 links lysosomal Ca²⁺ to autophagosome biogenesis by activating the CaMKKβ-AMPK-ULK1-VPS34 pathway and promoting PI3P-dependent recruitment of phagophore proteins^[2]. In disease models, TRPML1 loss causes mucolipidosis type IV, while TRPML1 activation improves α-synuclein aggregate clearance, rescues Alzheimer-related endosomal-autophagic-lysosomal defects, and reverses VacA-disrupted endolysosomal trafficking during Helicobacter pylori infection^[2][3][4][5]. Compared with related isoforms, TRPML3 acts as a PI3P effector in phagophores, whereas TRPML1 primarily controls late endolysosomal Ca²⁺ signaling and can form MCOLN1-MCOLN3 heteromers for autophagosome-lysosome fusion^[6][7]. For experimental applications, ML-SA1 and ML1-SA1 activate TRPML1-dependent lysosomal Ca²⁺ signaling, whereas ML-SI3 and EDME-related antagonists support loss-of-function studies of autophagy, TFEB translocation, migration, invasion, and disease-relevant lysosomal trafficking^[3][4][8][9].