TPC1-dependent control of endosomal pH and transferrin uptake determines cellular iron status
- Rebecca Deutsch
- Simone Jörs
- Yvonne Klingl
- Veronika Kudrina
- Danusa Menegaz
- Dawid Jaślan
- Zala Serianz
- Andreas Vogel
- Carla Abrahamian
- Sayari Bhunia
- Tinatini Tavhelidse-Suck
- Christin Richter
- Angela Wirth
- Nicole Urban
- Bernd Northoff
- Wolfgang Wilfert
- Norbert Klugbauer
- Franz Bracher
- Marco Keller
- Fabian Geisler
- Michael Schaefer
- Daniel Teupser
- Lesca Holdt
- Serkan Belkaya
- Marc Freichel
- Christian Grimm
2026-08-05
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 I486T ) 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 2+ is being released via DMT1 in a H + dependent manner strongly depend on TPC1 activity.