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Mitoferrin is essential for erythroid iron assimilation


Iron has a fundamental role in many metabolic processes, including electron transport, deoxyribonucleotide synthesis, oxygen transport and many essential redox reactions involving haemoproteins and Fe–S cluster proteins. Defective iron homeostasis results in either iron deficiency or iron overload1. Precise regulation of iron transport in mitochondria is essential for haem biosynthesis2, haemoglobin production and Fe–S cluster protein assembly3,4 during red cell development. Here we describe a zebrafish mutant, frascati (frs)5, that shows profound hypochromic anaemia and erythroid maturation arrest owing to defects in mitochondrial iron uptake. Through positional cloning, we show that the gene mutated in the frs mutant is a member of the vertebrate mitochondrial solute carrier family (SLC25)6 that we call mitoferrin (mfrn). mfrn is highly expressed in fetal and adult haematopoietic tissues of zebrafish and mouse. Erythroblasts generated from murine embryonic stem cells null for Mfrn (also known as Slc25a37) show maturation arrest with severely impaired incorporation of 55Fe into haem. Disruption of the yeast mfrn orthologues, MRS3 and MRS4, causes defects in iron metabolism and mitochondrial Fe–S cluster biogenesis7,8,9,10. Murine Mfrn rescues the defects in frs zebrafish, and zebrafish mfrn complements the yeast mutant, indicating that the function of the gene may be highly conserved. Our data show that mfrn functions as the principal mitochondrial iron importer essential for haem biosynthesis in vertebrate erythroblasts.

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Figure 1: Analysis of the zebrafish frs mutation, the frs locus and expression of mfrn.
Figure 2: Mitochondrial localization of Mfrn and functional studies of the mfrn gene.
Figure 3: Phylogenetic relationship and expression pattern of mfrn and its paralogue, mfrn2.
Figure 4: The function of Mfrn in mitochondrial iron assimilation is conserved.


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

    CAS  Article  PubMed  Google Scholar 

  2. Napier, I., Ponka, P. & Richardson, D. R. Iron trafficking in the mitochondria: novel pathways revealed by disease. Blood 105, 1867–1874 (2005)

    CAS  Article  PubMed  Google Scholar 

  3. Lill, R. & Mühlenhoff, U. Iron-sulfur-protein biogenesis in eukaryotes. Trends Biochem. Sci. 30, 133–141 (2005)

    CAS  Article  PubMed  Google Scholar 

  4. Rouault, T. A. & Tong, W. H. Iron–sulphur cluster biogenesis and mitochondrial iron homeostasis. Nature Rev. Mol. Cell Biol. 6, 345–351 (2005)

    CAS  Article  Google Scholar 

  5. Ransom, D. G. et al. Characterization of zebrafish mutants with defects in embryonic hematopoiesis. Development 123, 311–319 (1996)

    CAS  PubMed  Google Scholar 

  6. Wohlrab, H. The human mitochondrial transport protein family: identification and protein regions significant for transport function and substrate specify. Biochim. Biophys. Acta 1709, 157–168 (2005)

    CAS  Article  PubMed  Google Scholar 

  7. Foury, F. & Roganti, T. Deletion of the mitochondrial carrier genes MRS3 and MRS4 suppresses mitochondrial iron accumulation in a yeast frataxin-deficient strain. J. Biol. Chem. 277, 24475–24483 (2002)

    CAS  Article  PubMed  Google Scholar 

  8. Mühlenhoff, U. et al. A specific role of the yeast mitochondrial carriers Mrs3/4p in mitochondrial iron acquisition under iron-limiting conditions. J. Biol. Chem. 278, 40612–40620 (2003)

    Article  PubMed  Google Scholar 

  9. Li, L. & Kaplan, J. A mitochondrial–vacuolar signalling pathway in yeast that affects iron and copper metabolism. J. Biol. Chem. 279, 33653–33661 (2004)

    CAS  Article  PubMed  Google Scholar 

  10. Zhang, Y., Lyver, E. R., Knight, S. A. B., Lesuisse, E. & Dancis, A. Frataxin and mitochondrial carrier proteins, Mrs3p and Mrs4p, cooperate in providing iron for heme synthesis. J. Biol. Chem. 280, 19794–19807 (2005)

    CAS  Article  PubMed  Google Scholar 

  11. Shafizadeh, E. & Paw, B. H. Zebrafish as a model of human hematologic disorders. Curr. Opin. Hematol. 11, 255–261 (2004)

    CAS  Article  PubMed  Google Scholar 

  12. Griffin, K. J., Amacher, S. L., Kimmel, C. B. & Kimelman, D. Molecular identification of spadetail regulation of zebrafish trunk and tail mesoderm formation by the T-box genes. Development 125, 3379–3388 (1998)

    CAS  PubMed  Google Scholar 

  13. Traver, D. et al. Transplantation and in vivo imaging of multilineage engraftment in zebrafish bloodless mutants. Nature Immunol. 4, 1238–1246 (2003)

    CAS  Article  Google Scholar 

  14. Kobayashi, K. et al. The gene mutated in adult-onset type II citrullinaemia encodes a putative mitochondrial carrier protein. Nature Genet. 22, 159–163 (1999)

    CAS  Article  PubMed  Google Scholar 

  15. Rosenberg, M. J. et al. Mutant deoxynucleotide carrier is associated with congenital microcephaly. Nature Genet. 32, 175–179 (2002)

    CAS  Article  PubMed  Google Scholar 

  16. Cantor, A. B. & Orkin, S. H. Hematopoietic development: a balancing act. Curr. Opin. Genet. Dev. 11, 513–519 (2001)

    CAS  Article  PubMed  Google Scholar 

  17. Lyons, S. E. et al. A nonsense mutation in zebrafish gata1 causes the bloodless phenotype in vlad tepes. Proc. Natl Acad. Sci. USA 99, 5454–5459 (2002)

    ADS  CAS  Article  PubMed  PubMed Central  Google Scholar 

  18. Nasevicius, A. & Ekker, S. C. Effective targeted gene ‘knockdown’ in zebrafish. Nature Genet. 26, 216–220 (2000)

    CAS  Article  PubMed  Google Scholar 

  19. Li, F. Y. et al. Characterization of a novel human putative mitochondrial transporter homologous to the yeast mitochondrial RNA splicing proteins 3 and 4. FEBS Lett. 494, 79–84 (2001)

    ADS  CAS  Article  PubMed  Google Scholar 

  20. Li, F. Y., Leibiger, B., Leibiger, I. & Larsson, C. Characterization of a putative murine mitochondrial transporter homology to hMRS3/4. Mamm. Genome 13, 20–23 (2002)

    CAS  Article  PubMed  Google Scholar 

  21. Li, Q. Z. et al. Rapid decrease of RNA level of a novel mouse mitochondrial solute carrier protein (Mscp) gene at 4–5 weeks of age. Mamm. Genome 12, 830–836 (2001)

    CAS  PubMed  Google Scholar 

  22. Gregory, T. et al. GATA-1 and erythropoietin cooperate to promote erythroid cell survival by regulating bcl-xL expression. Blood 94, 87–96 (1999)

    CAS  PubMed  Google Scholar 

  23. Cantor, A. B., Katz, S. G. & Orkin, S. H. Distinct domains of the GATA-1 cofactor FOG-1 differentially influence erythroid versus megakaryocytic maturation. Mol. Cell. Biol. 22, 4268–4279 (2002)

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  24. Sturrock, A., Alexander, J., Lamb, J., Craven, C. M. & Kaplan, J. Characterization of a transferrin-independent uptake system for iron in HeLa cells. J. Biol. Chem. 265, 3139–3145 (1990)

    CAS  PubMed  Google Scholar 

  25. Balzan, R., Bannister, W. H., Hunter, G. J. & Bannister, J. V. Escherichia coli iron superoxide dismutase targeted to the mitochondria of yeast cells protects the cells against oxidative stress. Proc. Natl Acad. Sci. USA 92, 4219–4223 (1995)

    ADS  CAS  Article  PubMed  PubMed Central  Google Scholar 

  26. Surinya, K. H., Cox, T. C. & May, B. K. Transcriptional regulation of the human erythroid 5-aminolevulinate synthase gene. J. Biol. Chem. 272, 26585–26594 (1997)

    CAS  Article  PubMed  Google Scholar 

  27. Paw, B. H. et al. Cell-specific mitotic defect and dyserythropoiesis associated with erythroid band 3 deficiency. Nature Genet. 34, 59–64 (2003)

    CAS  Article  PubMed  Google Scholar 

  28. Iuchi, I. & Yamamoto, M. Erythropoiesis in the developing rainbow trout, Salmo gairdneri irideus: histological and immunochemical detection of erythropoietic organs. J. Exp. Zool. 226, 409–417 (1983)

    CAS  Article  PubMed  Google Scholar 

  29. McKee, A. et al. A genome-wide in situ hybridization map of RNA-binding proteins reveals anatomically restricted expression in the developing mouse brain. BMC Dev. Biol. 5, 14 (2005)

    Article  PubMed  PubMed Central  Google Scholar 

  30. Roy, C. N., Penny, D. M., Feder, J. N. & Enns, C. A. The hereditary hemochromatosis protein, HFE, specifically regulates transferrin-mediated iron uptake in HeLa cells. J. Biol. Chem. 274, 9022–9028 (1999)

    CAS  Article  PubMed  Google Scholar 

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We thank C. Lawrence, A. Walker and C. Belair for zebrafish animal husbandry; M. Halpern for sptb333 zebrafish; S. Johnson for SJD zebrafish; W. Shu Wu for mouse bone marrow cDNA; C. Roy for advice on preparing 55Fe-saturated transferrin; M. Kaku and Y. Fujiwara for advice on ES cell culture and selection; H. Wohlrab for advice on SLC25 biochemistry; K. Dooley for the frsij001 allele from the Tübingen 2000 screen; M. Ocaña for help with confocal fluorescence images; S. Dallaire and C. Lee for karyotyping the Mfrn-null ES cells; A. B. Cantor for advice on generating Hox-11-immortalized haematopoietic cells; and E. Shafizadeh, S.-K. Choe, C. Burns, Y. Houvras, D. Langenau, W. Tse, H. Wolhrab, J. Kanki and G. M. Shaw for critically reading the manuscript. This work was supported in part by the William Randolph Hearst Foundation (B.H.P.); the March of Dimes Birth Defects Foundation Basil O'Connor Award (B.H.P.); the Swiss National Science Foundation (G.E.A.); the Belgian National Research Fund (E.M.); the NIH (L.L.P., L.I.Z., J.K., M.J.W., B.H.P.); and the Howard Hughes Medical Institute (L.I.Z.).

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Correspondence to Barry H. Paw.

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Competing interests

Sequences have been deposited in GenBank as follows: Zebrafish mfrn (slc25a37; DQ112224, DQ112225), Zebrafish mfrn2 (slc25a28; BC054641), mouse Mfrn (Slc25a37; AF361699), mouse Mfrn2 (Slc25a28; BC025908.1), human MFRN (MSCP; SLC25A37; NM_016612) and human MFRN2 (SLC25A28; BC058937). Reprints and permissions information is available at The authors declare no competing financial interests.

Supplementary information

Supplementary Figure 1.

Analysis of the frs anemic phenotype and the expression of mfrn in zebrafish (PDF 316 kb)

Supplementary Figure 2.

Expression pattern of murine Mfrn in cultured cells and zebrafish mfrn2 in developing embryos. (PDF 363 kb)

Supplementary Figure 3.

Biochemical characterization of mfrn-deficient mouse hematopoietic cells and yeasts. (PDF 221 kb)

Supplementary Figure 4.

Zebrafish mfrn corrects the mitochondrial iron deficiency of yeast Δmrs3/4 mutant. (PDF 240 kb)

Supplementary Figure Legends

Text to accompany the above Supplementary Figures. (DOC 27 kb)

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Shaw, G., Cope, J., Li, L. et al. Mitoferrin is essential for erythroid iron assimilation. Nature 440, 96–100 (2006).

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