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Nature advance online publication 14 September 2008 | doi:10.1038/nature07311
The type IV mucolipidosis-associated protein TRPML1 is an endolysosomal iron release channel
Xian-Ping Dong1, Xiping Cheng1, Eric Mills1, Markus Delling2, Fudi Wang3, Tino Kurz4 & Haoxing Xu1
1 The Department of Molecular, Cellular, and Developmental Biology, The University of Michigan, 3089 Natural Science Building (Kraus), 830 North University, Ann Arbor, Michigan 48109, USA
2 The Department of Cardiology, Children's Hospital Boston, Enders 1350, 320 Longwood Avenue, Boston, Massachusetts 02115, USA
3 Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 200031, China
4 Department of Pharmacology, Faculty of Health Science, University of Link?ping, S-58185 Link?ping, Sweden
TRPML1 (mucolipin 1, also known as MCOLN1) is predicted to be an intracellular late endosomal and lysosomal ion channel protein that belongs to the mucolipin subfamily of transient receptor potential (TRP) proteins1,2, 3. Mutations in the human TRPML1 gene cause mucolipidosis type IV disease (ML4)4, 5. ML4 patients have motor impairment, mental retardation, retinal degeneration and iron-deficiency anaemia. Because aberrant iron metabolism may cause neural and retinal degeneration6, 7, it may be a primary cause of ML4 phenotypes. In most mammalian cells, release of iron from endosomes and lysosomes after iron uptake by endocytosis of Fe3+-bound transferrin receptors6, or after lysosomal degradation of ferritin–iron complexes and autophagic ingestion of iron-containing macromolecules6, 8, is the chief source of cellular iron. The divalent metal transporter protein DMT1 (also known as SLC11A2) is the only endosomal Fe2+ transporter known at present and it is highly expressed in erythroid precursors6, 9. Genetic studies, however, suggest the existence of a DMT1-independent endosomal and lysosomal Fe2+transport protein9. By measuring radiolabelled iron uptake, by monitoring the levels of cytosolic and intralysosomal iron and by directly patch-clamping the late endosomal and lysosomal membrane, here we show that TRPML1 functions as a Fe2+ permeable channel in late endosomes and lysosomes. ML4 mutations are shown to impair the ability of TRPML1 to permeate Fe2+ at varying degrees, which correlate well with the disease severity. A comparison of TRPML1 -/- ML4 and control human skin fibroblasts showed a reduction in cytosolic Fe2+ levels, an increase in intralysosomal Fe2+ levels and an accumulation of lipofuscin-like molecules in TRPML1 -/- cells. We propose that TRPML1 mediates a mechanism by which Fe2+ is released from late endosomes and lysosomes. Our results indicate that impaired iron transport may contribute to both haematological and degenerative symptoms of ML4 patients.
