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Natl. Acad. Sci. U.S.A."],"published-print":{"date-parts":[[2026,7,21]]},"abstract":"<jats:p>\n                    Two-pore channel 1 (TPC1) is an endosomal Na\n                    <jats:sup>+<\/jats:sup>\n                    \/Ca\n                    <jats:sup>2+<\/jats:sup>\n                    -selective channel implicated in membrane trafficking, endosome tubulation, and excitability, but how TPC1 regulates membrane trafficking is unknown. Using TPC1-null human cells, we demonstrate that TPC1 drives transferrin receptor (TfR) trafficking and recycling via Ca\n                    <jats:sup>2+<\/jats:sup>\n                    , and not Na\n                    <jats:sup>+<\/jats:sup>\n                    fluxes or endosomal pH changes, since channel-targeted Ca\n                    <jats:sup>2+<\/jats:sup>\n                    -buffers inhibited trafficking, whereas a Na\n                    <jats:sup>+<\/jats:sup>\n                    -deficient Ca\n                    <jats:sup>2+<\/jats:sup>\n                    -permeable TPC1 mutant fully supported trafficking. TPC1 was unique since other Ca\n                    <jats:sup>2+<\/jats:sup>\n                    sources did not support TfR trafficking. TPC1 activity depended on the lipid PI(3,5)P\n                    <jats:sub>2<\/jats:sub>\n                    , since trafficking was impaired by a lipid-insensitive TPC1 or inhibitors of lipid synthesis. Finally, a corollary of this reduced TfR trafficking is an iron-deficiency and storage phenotype in TPC1-deficient HeLa cells and mice. Our findings highlight endosomes as unique Ca\n                    <jats:sup>2+<\/jats:sup>\n                    stores mobilized by a phosphoinositide-induced TPC1 channel that generates local Ca\n                    <jats:sup>2+<\/jats:sup>\n                    nanodomains crucial for maintaining TfR trafficking and consequent iron homeostasis.\n                  <\/jats:p>","DOI":"10.1073\/pnas.2530835123","type":"journal-article","created":{"date-parts":[[2026,7,15]],"date-time":"2026-07-15T16:19:51Z","timestamp":1784132391000},"update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":0,"title":["Endosomal TPC1\u2013mediated Ca\n                    <sup>2+<\/sup>\n                    nanodomains regulate transferrin receptor trafficking and iron homeostasis"],"prefix":"10.1073","volume":"123","author":[{"ORCID":"https:\/\/orcid.org\/0009-0000-3984-548X","authenticated-orcid":false,"given":"William 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