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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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.).

Author information

Author notes

    • George C. Shaw

    Present address: Ohio State University College of Medicine, Columbus, Ohio, 43210, USA

    • John J. Cope

    Present address: University at Buffalo School of Medicine and Biomedical Sciences, Buffalo, New York, 14214, USA

    • Gabriele E. Ackermann

    Present address: Kinderspital Zürich, Zürich, 8032, Switzerland

    • Rebecca A. Wingert

    Present address: Massachusetts General Hospital, Boston, Massachusetts, 02114, USA

    • David Traver

    Present address: University of California, San Diego, California, 92093, USA

    • Nikolaus S. Trede

    Present address: University of Utah, Salt Lake City, Utah, 84112, USA

    • Alison Brownlie

    Present address: Xenon Pharmaceuticals, Burnaby, British Columbia, V5G 4W8, Canada


  1. Division of Hematology, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, 02115, USA

    • George C. Shaw
    • , John J. Cope
    • , Kenneth Corson
    • , Gabriele E. Ackermann
    • , Emmanuel Minet
    •  & Barry H. Paw
  2. Department of Pathology, University of Utah School of Medicine, Salt Lake City, Utah, 84132, USA

    • Liangtao Li
    •  & Jerry Kaplan
  3. Howard Hughes Medical Institute, Stem Cell Program and Division of Hematology-Oncology, Children's Hospital Boston, Harvard Medical School, Boston, Massachusetts, 02115, USA

    • Candace Hersey
    • , Rebecca A. Wingert
    • , David Traver
    • , Nikolaus S. Trede
    • , Bruce A. Barut
    • , Yi Zhou
    • , Adriana Donovan
    • , Alison Brownlie
    •  & Leonard I. Zon
  4. The Jackson Laboratory, Bar Harbor, Maine, 04609, USA

    • Babette Gwynn
    • , Amy J. Lambert
    •  & Luanne L. Peters
  5. Department of Physiology and Biochemistry, University of Malta, MSD 06, Msida, Malta

    • Rena Balzan
  6. Division of Hematology, Department of Pediatrics, Children's Hospital of Philadelphia, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania, 19104, USA

    • Mitchell J. Weiss


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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.

Corresponding author

Correspondence to Barry H. Paw.

Supplementary information

  1. Supplementary Figure 1.

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

  2. Supplementary Figure 2.

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

  3. Supplementary Figure 3.

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

  4. Supplementary Figure 4.

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

  5. Supplementary Figure Legends

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

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