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

Nature volume 455, pages 992–996 (2008)Cite this article

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) 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.

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Figure 1: TRPML1 Va -expressing cells have a constitutively active H + -modulated Fe 2+ current.
Figure 2: Fe 2+ permeability of the TRPML1 channel is impaired by ML4 mutations.
Figure 3: TRPML1 conducts Fe 2+ in late endosomes and lysosomes.
Figure 4: TRPML1-deficient cells have reduced free (chelatable) iron levels and lysosomal autofluorescence.

References

  1. Venkatachalam, K., Hofmann, T. & Montell, C. Lysosomal localization of TRPML3 depends on TRPML2 and the mucolipidosis-associated protein TRPML1. J. Biol. Chem. 281, 17517–17527 (2006)

    Article  CAS  Google Scholar 

  2. Clapham, D. E. TRP channels as cellular sensors. Nature 426, 517–524 (2003)

    Article  ADS  CAS  Google Scholar 

  3. Nilius, B., Owsianik, G., Voets, T. & Peters, J. A. Transient receptor potential cation channels in disease. Physiol. Rev. 87, 165–217 (2007)

    Article  CAS  Google Scholar 

  4. Bassi, M. T. et al. Cloning of the gene encoding a novel integral membrane protein, mucolipidin-and identification of the two major founder mutations causing mucolipidosis type IV. Am. J. Hum. Genet. 67, 1110–1120 (2000)

    Article  CAS  Google Scholar 

  5. Sun, M. et al. Mucolipidosis type IV is caused by mutations in a gene encoding a novel transient receptor potential channel. Hum. Mol. Genet. 9, 2471–2478 (2000)

    Article  CAS  Google Scholar 

  6. Hentze, M. W., Muckenthaler, M. U. & Andrews, N. C. Balancing acts: molecular control of mammalian iron metabolism. Cell 117, 285–297 (2004)

    Article  CAS  Google Scholar 

  7. Lee, D. W., Andersen, J. K. & Kaur, D. Iron dysregulation and neurodegeneration: the molecular connection. Mol. Interv. 6, 89–97 (2006)

    Article  CAS  Google Scholar 

  8. Kidane, T. Z., Sauble, E. & Linder, M. C. Release of iron from ferritin requires lysosomal activity. Am. J. Physiol. Cell Physiol. 291, C445–C455 (2006)

    Article  CAS  Google Scholar 

  9. Gunshin, H. et al. Slc11a2 is required for intestinal iron absorption and erythropoiesis but dispensable in placenta and liver. J. Clin. Invest. 115, 1258–1266 (2005)

    Article  CAS  Google Scholar 

  10. Pryor, P. R., Reimann, F., Gribble, F. M. & Luzio, J. P. Mucolipin-1 is a lysosomal membrane protein required for intracellular lactosylceramide traffic. Traffic 7, 1388–1398 (2006)

    Article  CAS  Google Scholar 

  11. Xu, H., Delling, M., Li, L., Dong, X. & Clapham, D. E. Activating mutation in a mucolipin transient receptor potential channel leads to melanocyte loss in varitint-waddler mice. Proc. Natl Acad. Sci. USA 104, 18321–18326 (2007)

    Article  ADS  CAS  Google Scholar 

  12. Di Palma, F. et al. Mutations in Mcoln3 associated with deafness and pigmentation defects in varitint-waddler (Va) mice. Proc. Natl Acad. Sci. USA 99, 14994–14999 (2002)

    Article  ADS  CAS  Google Scholar 

  13. Altarescu, G. et al. The neurogenetics of mucolipidosis type IV. Neurology 59, 306–313 (2002)

    Article  CAS  Google Scholar 

  14. Goldin, E. et al. Transfer of a mitochondrial DNA fragment to MCOLN1 causes an inherited case of mucolipidosis IV. Hum. Mutat. 24, 460–465 (2004)

    Article  CAS  Google Scholar 

  15. Bargal, R., Goebel, H. H., Latta, E. & Bach, G. Mucolipidosis IV: novel mutation and diverse ultrastructural spectrum in the skin. Neuropediatrics 33, 199–202 (2002)

    Article  CAS  Google Scholar 

  16. Kress, G. J., Dineley, K. E. & Reynolds, I. J. The relationship between intracellular free iron and cell injury in cultured neurons, astrocytes, and oligodendrocytes. J. Neurosci. 22, 5848–5855 (2002)

    Article  CAS  Google Scholar 

  17. Petrat, F., de Groot, H. & Rauen, U. Determination of the chelatable iron pool of single intact cells by laser scanning microscopy. Arch. Biochem. Biophys. 376, 74–81 (2000)

    Article  CAS  Google Scholar 

  18. Goldin, E., Blanchette-Mackie, E. J., Dwyer, N. K., Pentchev, P. G. & Brady, R. O. Cultured skin fibroblasts derived from patients with mucolipidosis 4 are auto-fluorescent. Pediatr. Res. 37, 687–692 (1995)

    Article  CAS  Google Scholar 

  19. Kurz, T., Terman, A., Gustafsson, B. & Brunk, U. T. Lysosomes in iron metabolism, ageing and apoptosis. Histochem. Cell Biol. 129, 389–406 (2008)

    Article  CAS  Google Scholar 

  20. Chen, C. S., Bach, G. & Pagano, R. E. Abnormal transport along the lysosomal pathway in mucolipidosis, type IV disease. Proc. Natl Acad. Sci. USA 95, 6373–6378 (1998)

    Article  ADS  CAS  Google Scholar 

  21. Zeevi, D. A., Frumkin, A. & Bach, G. TRPML and lysosomal function. Biochim. Biophys. Acta. 1772, 851–858 (2007)

    Article  CAS  Google Scholar 

  22. Andrews, N. C. & Schmidt, P. J. Iron homeostasis. Annu. Rev. Physiol. 69, 69–85 (2007)

    Article  CAS  Google Scholar 

  23. Cerny, J. et al. The small chemical vacuolin-1 inhibits Ca2+-dependent lysosomal exocytosis but not cell resealing. EMBO Rep. 5, 883–888 (2004)

    Article  CAS  Google Scholar 

  24. Saito, M., Hanson, P. I. & Schlesinger, P. Luminal chloride-dependent activation of endosome calcium channels: patch clamp study of enlarged endosomes. J. Biol. Chem. 282, 27327–27333 (2007)

    Article  CAS  Google Scholar 

  25. Xu, H., Jin, J., DeFelice, L. J., Andrews, N. C. & Clapham, D. E. A spontaneous, recurrent mutation in divalent metal transporter-1 exposes a calcium entry pathway. PLoS Biol. 2, E50 (2004)

    Article  Google Scholar 

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Acknowledgements

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.

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Authors and Affiliations

  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,

    Xian-Ping Dong, Xiping Cheng, Eric Mills & Haoxing Xu

  2. The Department of Cardiology, Children’s Hospital Boston, Enders 1350, 320 Longwood Avenue, Boston, Massachusetts 02115, USA,

    Markus Delling

  3. Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 200031, China

    Fudi Wang

  4. Department of Pharmacology, Faculty of Health Science, University of Linköping, S-58185 Linköping, Sweden

    Tino Kurz

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  1. Xian-Ping Dong
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Correspondence to Haoxing Xu.

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Dong, XP., Cheng, X., Mills, E. et al. The type IV mucolipidosis-associated protein TRPML1 is an endolysosomal iron release channel. Nature 455, 992–996 (2008). https://doi.org/10.1038/nature07311

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