Proceedings of the National Academy of Sciences of the United States of America · 2026
TPC1-dependent control of endosomal pH and transferrin uptake determines cellular iron status.
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Deutsch Rebecca, Jörs Simone, Klingl Yvonne, Kudrina Veronika, Menegaz Danusa, Jaślan 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
Аннотация
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.