TPCN1 encodes two-pore channel 1 (TPC1), an endolysosomal ion channel that mediates calcium and sodium transport across acidic organelle membranes. TPC1 functions as a NAADP-sensitive calcium-release channel and PI(3,5)P2-activated sodium channel with ligand-dependent selectivity 1. The channel exhibits dual activation modes: N-type activation via NAADP (requiring auxiliary proteins JPT2 and Lsm12) and P-type activation via PI(3,5)P2 1. Mechanistically, TPCN1 generates localized, non-propagating calcium transients from endolysosomes that regulate intracellular trafficking and membrane contact events 2. During viral infection, TPC1 controls endosomal movement required for Ebola virus escape into the cytoplasm 1. The channel modulates critical cellular processes including autophagy, exocytosis, endocytosis, and cholesterol trafficking 1. Diseased-associated roles include Ebola and COVID-19 infection, cancer, and neurodegenerative lysosomal storage diseases 1. In cardiac disease, TPCN1 expression patterns vary contextually—downregulated with other mitophagy genes in some heart failure models, yet unchanged in others 3. TPCN1 variants associate with Alzheimer's disease-related tau neuropathology and cognitive resilience 45. Additionally, paternal preconception smoking associates with TPCN1 promoter hypermethylation in offspring, correlating with respiratory and metabolic outcomes 6. TPCN1 requires further curation for definitive cardiomyopathy associations 7.