The type IV mucolipidosis-associated protein TRPML1 is an endolysosomal iron release channel
dc.contributor.author | Dong, Xian-Ping | en_US |
dc.contributor.author | Cheng, Xiping | en_US |
dc.contributor.author | Mills, Eric | en_US |
dc.contributor.author | Delling, Markus | en_US |
dc.contributor.author | Wang, Fudi | en_US |
dc.contributor.author | Kurz, Tino | en_US |
dc.contributor.author | Xu, Haoxing | en_US |
dc.date.accessioned | 2009-06-01T17:30:44Z | |
dc.date.available | 2009-06-01T17:30:44Z | |
dc.date.issued | 2008-10-16 | en_US |
dc.identifier.citation | Dong, Xian-Ping; Cheng, Xiping; Mills, Eric; Delling, Markus; Wang, Fudi; Kurz, Tino; Xu, Haoxing. (2008) "The type IV mucolipidosis-associated protein TRPML1 is an endolysosomal iron release channel." Nature 455(7215): 992-U78. <http://hdl.handle.net/2027.42/62672> | en_US |
dc.identifier.issn | 0028-0836 | en_US |
dc.identifier.uri | https://hdl.handle.net/2027.42/62672 | |
dc.identifier.uri | http://www.ncbi.nlm.nih.gov/sites/entrez?cmd=retrieve&db=pubmed&list_uids=18794901&dopt=citation | en_US |
dc.description.abstract | 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 Fe3+- 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 Fe2+ 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 Fe2+ 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 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 transportmay contribute to both haematological and degenerative symptoms of ML4 patients. | en_US |
dc.description.sponsorship | Department of Molecular, Cellular ; Developmental Biology and Biological Science Scholar Program ; University of Michigan | en_US |
dc.description.sponsorship | This work is supported by start-up funds to H. X. from the Department of Molecular, Cellular, and Developmental Biology and Biological Science Scholar Program, University of Michigan. We thank U. Brunk, M. Saito, R. Hume, C. Duan, M. Akaaboune, J. Kuwada, S. Low, S. Punthambaker and S. Dellal for assistance, and D. Clapham, N. Andrews, L. DeFelice, L. Yue, D. Ren, C. Jiang and S. Xu for comments on an earlier version of the manuscript. We also thank K. Kiselyov for sharing his unpublished results on lysosomal iron staining of ML4 cells. We appreciate the encouragement and helpful comments from other members of the Xu laboratory. | en_US |
dc.format.extent | 1019062 bytes | |
dc.format.extent | 2489 bytes | |
dc.format.mimetype | application/pdf | |
dc.format.mimetype | text/plain | |
dc.publisher | Nature Publishing Group | en_US |
dc.source | Nature | en_US |
dc.title | The type IV mucolipidosis-associated protein TRPML1 is an endolysosomal iron release channel | en_US |
dc.type | Article | en_US |
dc.subject.hlbtoplevel | Science | en_US |
dc.description.peerreviewed | Peer Reviewed | en_US |
dc.contributor.affiliationum | Xu, Haoxing] Univ Michigan, Dept Mol Cellular & Dev Biol, Ann Arbor, MI 48109 USA | en_US |
dc.contributor.affiliationother | [Dong, Xian-Ping | en_US |
dc.contributor.affiliationother | Cheng, Xiping | en_US |
dc.contributor.affiliationother | Mills, Eric | en_US |
dc.contributor.affiliationother | [Delling, Markus] Childrens Hosp, Dept Cardiol, Boston, MA 02115 USA | en_US |
dc.contributor.affiliationother | [Wang, Fudi] Chinese Acad Sci, Inst Nutr Sci, Shanghai Inst Biol Sci, Shanghai 200031, Peoples R China | en_US |
dc.contributor.affiliationother | [Kurz, Tino] Linkoping Univ, Dept Pharmacol, Fac Hlth Sci, S-58185 Linkoping, Sweden | en_US |
dc.identifier.pmid | 18794901 | en_US |
dc.description.bitstreamurl | http://deepblue.lib.umich.edu/bitstream/2027.42/62672/1/nature07311.pdf | |
dc.identifier.doi | http://dx.doi.org/10.1038/nature07311 | en_US |
dc.identifier.source | Nature | en_US |
dc.contributor.authoremail | haoxingx@umich.edu | en_US |
dc.owningcollname | Interdisciplinary and Peer-Reviewed |
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