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Mitoferrin is essential for erythroid iron assimilation

Author

Listed:
  • George C. Shaw

    (Harvard Medical School
    Ohio State University College of Medicine)

  • John J. Cope

    (Harvard Medical School
    University at Buffalo School of Medicine and Biomedical Sciences)

  • Liangtao Li

    (University of Utah School of Medicine)

  • Kenneth Corson

    (Harvard Medical School)

  • Candace Hersey

    (Harvard Medical School)

  • Gabriele E. Ackermann

    (Harvard Medical School
    Kinderspital Zürich)

  • Babette Gwynn

    (The Jackson Laboratory)

  • Amy J. Lambert

    (The Jackson Laboratory)

  • Rebecca A. Wingert

    (Harvard Medical School
    Massachusetts General Hospital)

  • David Traver

    (Harvard Medical School
    University of California)

  • Nikolaus S. Trede

    (Harvard Medical School
    University of Utah)

  • Bruce A. Barut

    (Harvard Medical School)

  • Yi Zhou

    (Harvard Medical School)

  • Emmanuel Minet

    (Harvard Medical School)

  • Adriana Donovan

    (Harvard Medical School)

  • Alison Brownlie

    (Harvard Medical School
    Xenon Pharmaceuticals)

  • Rena Balzan

    (University of Malta)

  • Mitchell J. Weiss

    (University of Pennsylvania School of Medicine)

  • Luanne L. Peters

    (The Jackson Laboratory)

  • Jerry Kaplan

    (University of Utah School of Medicine)

  • Leonard I. Zon

    (Harvard Medical School)

  • Barry H. Paw

    (Harvard Medical School)

Abstract

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.

Suggested Citation

  • George C. Shaw & John J. Cope & Liangtao Li & Kenneth Corson & Candace Hersey & Gabriele E. Ackermann & Babette Gwynn & Amy J. Lambert & Rebecca A. Wingert & David Traver & Nikolaus S. Trede & Bruce A, 2006. "Mitoferrin is essential for erythroid iron assimilation," Nature, Nature, vol. 440(7080), pages 96-100, March.
    • Handle: RePEc:nat:nature:v:440:y:2006:i:7080:d:10.1038_nature04512
    DOI: 10.1038/nature04512
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    Cited by:

    1. Yan Yu Chen & Chun-Cheih Chao & Fu-Chen Liu & Po-Chen Hsu & Hsueh-Fen Chen & Shih-Chi Peng & Yung-Jen Chuang & Chung-Yu Lan & Wen-Ping Hsieh & David Shan Hill Wong, 2013. "Dynamic Transcript Profiling of Candida albicans Infection in Zebrafish: A Pathogen-Host Interaction Study," PLOS ONE, Public Library of Science, vol. 8(9), pages 1-16, September.
    2. Michał Szklarz & Katarzyna Gontarz-Nowak & Wojciech Matuszewski & Elżbieta Bandurska-Stankiewicz, 2022. "Can Iron Play a Crucial Role in Maintaining Cardiovascular Health in the 21st Century?," IJERPH, MDPI, vol. 19(19), pages 1-32, September.
    3. Xiaojian Shi & Bryn Reinstadler & Hardik Shah & Tsz-Leung To & Katie Byrne & Luanna Summer & Sarah E. Calvo & Olga Goldberger & John G. Doench & Vamsi K. Mootha & Hongying Shen, 2022. "Combinatorial GxGxE CRISPR screen identifies SLC25A39 in mitochondrial glutathione transport linking iron homeostasis to OXPHOS," Nature Communications, Nature, vol. 13(1), pages 1-15, December.

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