A mechanism of lysosomal calcium entry

Sci Adv. 2024 Feb 16;10(7):eadk2317. doi: 10.1126/sciadv.adk2317. Epub 2024 Feb 14.


Lysosomal calcium (Ca2+) release is critical to cell signaling and is mediated by well-known lysosomal Ca2+ channels. Yet, how lysosomes refill their Ca2+ remains hitherto undescribed. Here, from an RNA interference screen in Caenorhabditis elegans, we identify an evolutionarily conserved gene, lci-1, that facilitates lysosomal Ca2+ entry in C. elegans and mammalian cells. We found that its human homolog TMEM165, previously designated as a Ca2+/H+ exchanger, imports Ca2+ pH dependently into lysosomes. Using two-ion mapping and electrophysiology, we show that TMEM165, hereafter referred to as human LCI, acts as a proton-activated, lysosomal Ca2+ importer. Defects in lysosomal Ca2+ channels cause several neurodegenerative diseases, and knowledge of lysosomal Ca2+ importers may provide previously unidentified avenues to explore the physiology of Ca2+ channels.

MeSH terms

  • Animals
  • Antiporters / metabolism
  • Caenorhabditis elegans / metabolism
  • Calcium Channels / genetics
  • Calcium Channels / metabolism
  • Calcium Signaling
  • Calcium* / metabolism
  • Cation Transport Proteins* / metabolism
  • Humans
  • Lysosomes / metabolism
  • Mammals / metabolism
  • Signal Transduction


  • Calcium
  • Calcium Channels
  • TMEM165 protein, human
  • Antiporters
  • Cation Transport Proteins