TPC1-dependent control of endosomal pH and transferrin uptake determines cellular iron status

• 成果类型: Article
• 署名作者: Deutsch, Rebecca; Jors, Simone; Klingl, Yvonne; Kudrina, Veronika; Menegaz, Danusa; Jaslan, Dawid; Serianz, Zala; Vogel, Andreas; Abrahamian, Carla; Bhunia, Sayari; Tavhelidse-Suck, Tinatini; Richter, Christin; Wirth, Angela; Urban, Nicole; Northoff, Bernd; Wilfert, Wolfgang; Klugbauer, Norbert; Bracher, Franz; Keller, Marco; Geisler, Fabian; Schaefer, Michael; Teupser, Daniel; Holdt, Lesca; Belkaya, Serkan; Freichel, Marc; Grimm, Christian
• 署名单位: University of Munich; University of Munich; Technical University of Munich; German Heart Centre Munich; Technical University of Munich; Ruprecht Karls University Heidelberg; Leipzig University; University of Munich; University of Freiburg; University of Munich; Ihsan Dogramaci Bilkent University; University of Oxford
• 刊物名称: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
• ISSN/ISSBN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.2602941123
• 发表日期: 2026-08-11
• 页码: e2602941123
• 关键词: TPC1; TPCN1; TPC; endosome; iron; ATPASE INHIBITION; 2-PORE CHANNELS; molecular-basis; Mutation; metabolism; homeostasis; deafness; leads

摘要

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 (TPC1I486T) 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 Fe2+ is being released via DMT1 in a H+ dependent manner strongly depend on TPC1 activity.