{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,7]],"date-time":"2026-08-07T14:31:00Z","timestamp":1786113060103,"version":"build-2736575974"},"reference-count":59,"publisher":"National Academy of Sciences","issue":"32","license":[{"start":{"date-parts":[[2026,8,5]],"date-time":"2026-08-05T00:00:00Z","timestamp":1785888000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"content-domain":{"domain":["www.pnas.org"],"crossmark-restriction":true},"short-container-title":["Proc. Natl. Acad. Sci. U.S.A."],"published-print":{"date-parts":[[2026,8,11]]},"abstract":"<jats:p>\n                    Iron overload is a life-threatening disease. Without early diagnosis and treatment, it can cause severe organ damage and even premature death by irreversibly damaging organs such as the heart, pancreas, spleen, or liver. We report here that a gain-of-function mutation in the endolysosomal two-pore channel TPC1 (TPC1\n                    <jats:sup>I486T<\/jats:sup>\n                    ) causes iron overload in mice, whereas mice lacking TPC1 exhibit the opposite phenotype, iron deficiency. Endolysosomal patch-clamp experiments demonstrated a strong gain in both human and mouse TPC1 mutant channel activity compared to wild-type upon activation with the early endosome (EE) associated endogenous ligand phosphatidylinositol 3-phosphate. Mechanistically, it was found that uptake of iron bound to transferrin\/transferrin receptor from the plasma membrane as well as the pH in EE, from where Fe\n                    <jats:sup>2+<\/jats:sup>\n                    is being released via DMT1 in a H\n                    <jats:sup>+<\/jats:sup>\n                    dependent manner strongly depend on TPC1 activity.\n                  <\/jats:p>","DOI":"10.1073\/pnas.2602941123","type":"journal-article","created":{"date-parts":[[2026,8,5]],"date-time":"2026-08-05T17:36:00Z","timestamp":1785951360000},"update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":0,"title":["TPC1-dependent control of endosomal pH and transferrin uptake determines cellular iron status"],"prefix":"10.1073","volume":"123","author":[{"ORCID":"https:\/\/orcid.org\/0009-0007-6737-7266","authenticated-orcid":false,"given":"Rebecca","family":"Deutsch","sequence":"first","affiliation":[{"id":[{"id":"https:\/\/ror.org\/02wbcav28","id-type":"ROR","asserted-by":"publisher"}],"name":"Walther Straub Institute of Pharmacology and Toxicology, Faculty of Medicine, Ludwig-Maximilians-University","place":["Munich, Germany"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Simone","family":"J\u00f6rs","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/05591te55","id-type":"ROR","asserted-by":"publisher"}],"name":"Technical University of Munich School of Medicine and Health, Department of Clinical Medicine\u2014Clinical Department for Internal Medicine II, University Medical Center, Technical University of Munich","place":["Munich, Germany"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yvonne","family":"Klingl","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/01s1h3j07","id-type":"ROR","asserted-by":"publisher"}],"name":"Immunology, Infection and Pandemic Research IIP, Fraunhofer Institute for Translational Medicine and Pharmacology ITMP","place":["Munich\/Frankfurt, Germany"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3762-8673","authenticated-orcid":false,"given":"Veronika","family":"Kudrina","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/02wbcav28","id-type":"ROR","asserted-by":"publisher"}],"name":"Walther Straub Institute of Pharmacology and Toxicology, Faculty of Medicine, Ludwig-Maximilians-University","place":["Munich, Germany"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0008-4340-5055","authenticated-orcid":false,"given":"Danusa","family":"Menegaz","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/01s1h3j07","id-type":"ROR","asserted-by":"publisher"}],"name":"Immunology, Infection and Pandemic Research IIP, Fraunhofer Institute for Translational Medicine and Pharmacology ITMP","place":["Munich\/Frankfurt, Germany"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0685-7633","authenticated-orcid":false,"given":"Dawid","family":"Ja\u015blan","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/02wbcav28","id-type":"ROR","asserted-by":"publisher"}],"name":"Walther Straub Institute of Pharmacology and Toxicology, Faculty of Medicine, Ludwig-Maximilians-University","place":["Munich, Germany"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0009-5753-3637","authenticated-orcid":false,"given":"Zala","family":"Serianz","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/02wbcav28","id-type":"ROR","asserted-by":"publisher"}],"name":"Walther Straub Institute of Pharmacology and Toxicology, Faculty of Medicine, Ludwig-Maximilians-University","place":["Munich, Germany"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0008-5644-7975","authenticated-orcid":false,"given":"Andreas","family":"Vogel","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/02wbcav28","id-type":"ROR","asserted-by":"publisher"}],"name":"Walther Straub Institute of Pharmacology and Toxicology, Faculty of Medicine, Ludwig-Maximilians-University","place":["Munich, Germany"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0425-8004","authenticated-orcid":false,"given":"Carla","family":"Abrahamian","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/02kkvpp62","id-type":"ROR","asserted-by":"publisher"}],"name":"Department of Cardiology, German Heart Centre Munich, Technical University of Munich","place":["Munich, Germany"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sayari","family":"Bhunia","sequence":"additional","affiliation":[{"name":"Institute of Pharmacology, Heidelberg University","place":["Heidelberg, Germany"]},{"id":[{"id":"https:\/\/ror.org\/031t5w623","id-type":"ROR","asserted-by":"publisher"}],"name":"German Centre for Cardiovascular Research, Partner Site Heidelberg\/Mannheim","place":["Heidelberg, Germany"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6103-9019","authenticated-orcid":false,"given":"Tinatini","family":"Tavhelidse-Suck","sequence":"additional","affiliation":[{"name":"Institute of Pharmacology, Heidelberg University","place":["Heidelberg, Germany"]},{"id":[{"id":"https:\/\/ror.org\/031t5w623","id-type":"ROR","asserted-by":"publisher"}],"name":"German Centre for Cardiovascular Research, Partner Site Heidelberg\/Mannheim","place":["Heidelberg, Germany"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christin","family":"Richter","sequence":"additional","affiliation":[{"name":"Institute of Pharmacology, Heidelberg University","place":["Heidelberg, Germany"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Angela","family":"Wirth","sequence":"additional","affiliation":[{"name":"Institute of Pharmacology, Heidelberg University","place":["Heidelberg, Germany"]},{"id":[{"id":"https:\/\/ror.org\/031t5w623","id-type":"ROR","asserted-by":"publisher"}],"name":"German Centre for Cardiovascular Research, Partner Site Heidelberg\/Mannheim","place":["Heidelberg, Germany"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5516-7922","authenticated-orcid":false,"given":"Nicole","family":"Urban","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/03s7gtk40","id-type":"ROR","asserted-by":"publisher"}],"name":"Rudolf-Boehm-Institute for Pharmacology and Toxicology, Universit\u00e4t Leipzig","place":["Leipzig, Germany"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7333-3231","authenticated-orcid":false,"given":"Bernd","family":"Northoff","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/05g1y0660","id-type":"ROR","asserted-by":"publisher"}],"name":"Institute of Laboratory Medicine, University Hospital Munich","place":["Munich, Germany"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wolfgang","family":"Wilfert","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/05g1y0660","id-type":"ROR","asserted-by":"publisher"}],"name":"Institute of Laboratory Medicine, University Hospital Munich","place":["Munich, Germany"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0553-9446","authenticated-orcid":false,"given":"Norbert","family":"Klugbauer","sequence":"additional","affiliation":[{"name":"Institute for Experimental and Clinical Pharmacology and Toxicology, Medical Faculty, Albert-Ludwigs-University Freiburg","place":["Freiburg, Germany"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0009-8629","authenticated-orcid":false,"given":"Franz","family":"Bracher","sequence":"additional","affiliation":[{"name":"Department of Pharmacy, Ludwig-Maximilians-University","place":["Munich, Germany"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4792-3980","authenticated-orcid":false,"given":"Marco","family":"Keller","sequence":"additional","affiliation":[{"name":"Department of Pharmacy, Ludwig-Maximilians-University","place":["Munich, Germany"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fabian","family":"Geisler","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/05591te55","id-type":"ROR","asserted-by":"publisher"}],"name":"Technical University of Munich School of Medicine and Health, Department of Clinical Medicine\u2014Clinical Department for Internal Medicine II, University Medical Center, Technical University of Munich","place":["Munich, Germany"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael","family":"Schaefer","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/03s7gtk40","id-type":"ROR","asserted-by":"publisher"}],"name":"Rudolf-Boehm-Institute for Pharmacology and Toxicology, Universit\u00e4t Leipzig","place":["Leipzig, Germany"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daniel","family":"Teupser","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/05g1y0660","id-type":"ROR","asserted-by":"publisher"}],"name":"Institute of Laboratory Medicine, University Hospital Munich","place":["Munich, Germany"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lesca","family":"Holdt","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/05g1y0660","id-type":"ROR","asserted-by":"publisher"}],"name":"Institute of Laboratory Medicine, University Hospital Munich","place":["Munich, Germany"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Serkan","family":"Belkaya","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/02vh8a032","id-type":"ROR","asserted-by":"publisher"}],"name":"Department of Molecular Biology and Genetics, Bilkent University","place":["Ankara, T\u00fcrkiye"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1387-2636","authenticated-orcid":false,"given":"Marc","family":"Freichel","sequence":"additional","affiliation":[{"name":"Institute of Pharmacology, Heidelberg University","place":["Heidelberg, Germany"]},{"id":[{"id":"https:\/\/ror.org\/031t5w623","id-type":"ROR","asserted-by":"publisher"}],"name":"German Centre for Cardiovascular Research, Partner Site Heidelberg\/Mannheim","place":["Heidelberg, Germany"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0177-5559","authenticated-orcid":false,"given":"Christian","family":"Grimm","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/02wbcav28","id-type":"ROR","asserted-by":"publisher"}],"name":"Walther Straub Institute of Pharmacology and Toxicology, Faculty of Medicine, Ludwig-Maximilians-University","place":["Munich, Germany"]},{"id":[{"id":"https:\/\/ror.org\/01s1h3j07","id-type":"ROR","asserted-by":"publisher"}],"name":"Immunology, Infection and Pandemic Research IIP, Fraunhofer Institute for Translational Medicine and Pharmacology ITMP","place":["Munich\/Frankfurt, Germany"]},{"id":[{"id":"https:\/\/ror.org\/052gg0110","id-type":"ROR","asserted-by":"publisher"}],"name":"Department of Pharmacology, Faculty of Medicine, University of Oxford","place":["Oxford, United Kingdom"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"341","published-online":{"date-parts":[[2026,8,5]]},"reference":[{"key":"e_1_3_4_1_2","doi-asserted-by":"publisher","DOI":"10.1007\/978-3-030-62026-4_3"},{"key":"e_1_3_4_2_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbadis.2015.03.011"},{"key":"e_1_3_4_3_2","doi-asserted-by":"publisher","DOI":"10.1007\/978-3-031-92033-2_8"},{"key":"e_1_3_4_4_2","doi-asserted-by":"publisher","DOI":"10.1038\/nrdp.2018.16"},{"key":"e_1_3_4_5_2","doi-asserted-by":"publisher","DOI":"10.7554\/eLife.54712"},{"key":"e_1_3_4_6_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-022-31959-0"},{"key":"e_1_3_4_7_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2012.08.036"},{"key":"e_1_3_4_8_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41598-017-10607-4"},{"key":"e_1_3_4_9_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-024-54324-9"},{"key":"e_1_3_4_10_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2013.01.023"},{"key":"e_1_3_4_11_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1705739114"},{"key":"e_1_3_4_12_2","doi-asserted-by":"publisher","DOI":"10.3390\/cells11132006"},{"key":"e_1_3_4_13_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.ceb.2019.03.011"},{"key":"e_1_3_4_14_2","doi-asserted-by":"publisher","DOI":"10.1126\/scisignal.adg0485"},{"key":"e_1_3_4_15_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-021-24735-z"},{"key":"e_1_3_4_16_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.ceca.2023.102705"},{"key":"e_1_3_4_17_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-023-35786-9"},{"key":"e_1_3_4_18_2","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pgen.1009236"},{"key":"e_1_3_4_19_2","doi-asserted-by":"publisher","DOI":"10.1080\/15548627.2016.1190072"},{"key":"e_1_3_4_20_2","doi-asserted-by":"publisher","DOI":"10.1126\/science.1258758"},{"key":"e_1_3_4_21_2","doi-asserted-by":"publisher","DOI":"10.15252\/emmm.202115377"},{"key":"e_1_3_4_22_2","doi-asserted-by":"publisher","DOI":"10.1038\/nchembio.1522"},{"key":"e_1_3_4_23_2","doi-asserted-by":"publisher","DOI":"10.1038\/nature07311"},{"key":"e_1_3_4_24_2","doi-asserted-by":"publisher","DOI":"10.1083\/jcb.200904073"},{"key":"e_1_3_4_25_2","doi-asserted-by":"publisher","DOI":"10.1111\/jnc.15583"},{"key":"e_1_3_4_26_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41420-024-02026-y"},{"key":"e_1_3_4_27_2","doi-asserted-by":"publisher","DOI":"10.1111\/j.1432-1033.1982.tb19758.x"},{"key":"e_1_3_4_28_2","doi-asserted-by":"publisher","DOI":"10.1016\/S1471-4914(00)01910-9"},{"key":"e_1_3_4_29_2","doi-asserted-by":"publisher","DOI":"10.1080\/10245330500093419"},{"key":"e_1_3_4_30_2","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0002758"},{"key":"e_1_3_4_31_2","doi-asserted-by":"publisher","DOI":"10.1038\/ncb1348"},{"key":"e_1_3_4_32_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1600108113"},{"key":"e_1_3_4_33_2","doi-asserted-by":"publisher","DOI":"10.1038\/srep26570"},{"key":"e_1_3_4_34_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0021-9258(19)47429-2"},{"key":"e_1_3_4_35_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-021-22111-5"},{"key":"e_1_3_4_36_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.80.8.2258"},{"key":"e_1_3_4_37_2","doi-asserted-by":"publisher","DOI":"10.1158\/0008-5472.CAN-14-2097"},{"key":"e_1_3_4_38_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41598-025-89127-5"},{"key":"e_1_3_4_39_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M604592200"},{"key":"e_1_3_4_40_2","doi-asserted-by":"publisher","DOI":"10.1126\/scisignal.2004854"},{"key":"e_1_3_4_41_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0709846104"},{"key":"e_1_3_4_42_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0709096104"},{"key":"e_1_3_4_43_2","doi-asserted-by":"publisher","DOI":"10.1038\/emboj.2008.56"},{"key":"e_1_3_4_44_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0707963105"},{"key":"e_1_3_4_45_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.C700190200"},{"key":"e_1_3_4_46_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-021-27860-x"},{"key":"e_1_3_4_47_2","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0278848"},{"key":"e_1_3_4_48_2","doi-asserted-by":"publisher","DOI":"10.1007\/978-1-4939-9018-4_12"},{"key":"e_1_3_4_49_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.devcel.2013.08.003"},{"key":"e_1_3_4_50_2","doi-asserted-by":"publisher","DOI":"10.15252\/embj.2019104058"},{"key":"e_1_3_4_51_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.2309465121"},{"key":"e_1_3_4_52_2","doi-asserted-by":"publisher","DOI":"10.1083\/jcb.200107069"},{"key":"e_1_3_4_53_2","doi-asserted-by":"publisher","DOI":"10.1126\/science.aaw9544"},{"key":"e_1_3_4_54_2","doi-asserted-by":"publisher","DOI":"10.1172\/JCI169428"},{"key":"e_1_3_4_55_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.celrep.2023.112855"},{"key":"e_1_3_4_56_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M116.751529"},{"key":"e_1_3_4_57_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.aca.2004.06.030"},{"key":"e_1_3_4_58_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.xpro.2021.100831"},{"key":"e_1_3_4_59_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41598-026-40642-z"}],"container-title":["Proceedings of the National Academy of Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/pnas.org\/doi\/pdf\/10.1073\/pnas.2602941123","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,8,5]],"date-time":"2026-08-05T17:36:21Z","timestamp":1785951381000},"score":1,"resource":{"primary":{"URL":"https:\/\/pnas.org\/doi\/10.1073\/pnas.2602941123"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,8,5]]},"references-count":59,"journal-issue":{"issue":"32","published-print":{"date-parts":[[2026,8,11]]}},"alternative-id":["10.1073\/pnas.2602941123"],"URL":"https:\/\/doi.org\/10.1073\/pnas.2602941123","relation":{},"ISSN":["0027-8424","1091-6490"],"issn-type":[{"value":"0027-8424","type":"print"},{"value":"1091-6490","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,8,5]]},"assertion":[{"value":"2026-01-31","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2026-07-03","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2026-08-05","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}],"article-number":"e2602941123"}}