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

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) proteins(1-3). 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 degeneration(6,7), 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 Fe(3+)- bound transferrin receptors(6), or after lysosomal degradation of ferritin - iron complexes and autophagic ingestion of iron-containing macromolecules(6,8), is the chief source of cellular iron. The divalent metal transporter protein DMT1 ( also known as SLC11A2) is the only endosomal Fe(2+) transporter known at present and it is highly expressed in erythroid precursors(6,9). Genetic studies, however, suggest the existence of a DMT1-independent endosomal and lysosomal Fe(2+) transport protein(9). 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 Fe(2+) permeable channel in late endosomes and lysosomes. ML4 mutations are shown to impair the ability of TRPML1 to permeate Fe(2+) 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 Fe(2+) levels, an increase in intralysosomal Fe(2+) levels and an accumulation of lipofuscin- like molecules in TRPML1(-/-) cells. We propose that TRPML1 mediates a mechanism by which Fe(2+) is released from late endosomes and lysosomes. Our results indicate that impaired iron transportmay contribute to both haematological and degenerative symptoms of ML4 patients.