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 assembly^{3, 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 biogenesis^{7, 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.

1. Division of Hematology, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts 02115, USA
2. Department of Pathology, University of Utah School of Medicine, Salt Lake City, Utah 84132, USA
3. Howard Hughes Medical Institute, Stem Cell Program and Division of Hematology-Oncology, Children's Hospital Boston, Harvard Medical School, Boston, Massachusetts 02115, USA
4. The Jackson Laboratory, Bar Harbor, Maine 04609, USA
5. Department of Physiology and Biochemistry, University of Malta, Msida MSD 06, Malta
6. Division of Hematology, Department of Pediatrics, Children's Hospital of Philadelphia, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104, USA
7. †Present addresses: Ohio State University College of Medicine, Columbus, Ohio 43210, USA (G.C.S.); University at Buffalo School of Medicine and Biomedical Sciences, Buffalo, New York 14214, USA (J.J.C.); Kinderspital Zürich, Zürich 8032, Switzerland (G.E.A.); Massachusetts General Hospital, Boston, Massachusetts 02114, USA (R.A.W.); University of California, San Diego, California 92093, USA. (D.T.); University of Utah, Salt Lake City, Utah 84112, USA (N.S.T.); Xenon Pharmaceuticals, Burnaby, British Columbia V5G 4W8, Canada (A.B.)

Correspondence to: Barry H. Paw¹ Correspondence and requests for materials should be addressed to B.H.P. (Email: bpaw@rics.bwh.harvard.edu). 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).

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