The type IV mucolipidosis-associated protein TRPML1 is an endolysosomal iron release channel

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Abstract
Mutations in the human TRPML1 gene, a member of the transient receptor potential (TRP) superfamily of ion channels, cause mucolipidosis type IV disease. Symptoms of the condition include anaemia, psychomotor retardation and retinal degeneration. Xian-ping Dong et al. now show that TRPML1 acts as a Fe2+-permeable channel in lysosomes, and that disease-associated mutations impair Fe2+ transport. The work suggests that impaired iron transport underlies symptoms of mucolipidosis, including neurodegeneration, and that lysosome-targeting chelators might alleviate the degenerative symptoms of patients with mucolipidosis type IV. TRPML1 is a member of the Transient Receptor Potential (TRP) superfamily of ion channels, and mutation in the human TRPML1 gene causes mucolipidosis, symptoms of which include anaemia. It is shown that TRPML1 functions as a Fe2+-permeable channel in lysosomes, and that disease-associated mutations impair Fe2+transport, suggesting that impaired iron transport may underlie symptoms of mucolipidosis. 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.