Mitoferrin is essential for erythroid iron assimilation

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. Barut, Yi Zhou, Emmanuel Minet, Adriana Donovan, Alison Brownlie, Rena Balzan, Mitchell J. Weiss, Luanne L. Peters, Jerry Kaplan, Leonard I. Zon and Barry H. Paw ()
Additional contact information
George C. Shaw: Harvard Medical School
John J. Cope: Harvard Medical School
Liangtao Li: University of Utah School of Medicine
Kenneth Corson: Harvard Medical School
Candace Hersey: Harvard Medical School
Gabriele E. Ackermann: Harvard Medical School
Babette Gwynn: The Jackson Laboratory
Amy J. Lambert: The Jackson Laboratory
Rebecca A. Wingert: Harvard Medical School
David Traver: Harvard Medical School
Nikolaus S. Trede: Harvard Medical School
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
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

Nature, 2006, vol. 440, issue 7080, 96-100

Abstract: 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.

Date: 2006
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DOI: 10.1038/nature04512

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