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 overload. Precise regulation of iron transport in mitochondria is essential for haem biosynthesis, haemoglobin production and Fe-S cluster protein assembly during red cell development. Here we describe a zebrafish mutant, frascati (frs), 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) 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. 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.
Shaw
George C
GC
Division of Hematology, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts 02115, USA.
Cope
John J
JJ
Li
Liangtao
L
Corson
Kenneth
K
Hersey
Candace
C
Ackermann
Gabriele E
GE
Gwynn
Babette
B
Lambert
Amy J
AJ
Wingert
Rebecca A
RA
Traver
David
D
Trede
Nikolaus S
NS
Barut
Bruce A
BA
Zhou
Yi
Y
Minet
Emmanuel
E
Donovan
Adriana
A
Brownlie
Alison
A
Balzan
Rena
R
Weiss
Mitchell J
MJ
Peters
Luanne L
LL
Kaplan
Jerry
J
Zon
Leonard I
LI
Paw
Barry H
BH
D000740:Anemia / Q000097:blood / Q000378:metabolism; D000818:Animals; D027682:Cation Transport Proteins / Q000235:genetics / Q000378:metabolism; D002454:Cell Differentiation; D017124:Conserved Sequence; D004900:Erythroblasts / Q000166:cytology / Q000378:metabolism* / Q000473:pathology; D005786:Gene Expression Regulation; D005816:Genetic Complementation Test; D006418:Heme / Q000378:metabolism; D006706:Homeostasis; D006801:Humans; D007501:Iron / Q000378:metabolism*; D019190:Iron Overload; D007506:Iron-Sulfur Proteins / Q000096:biosynthesis / Q000235:genetics; D026901:Membrane Transport Proteins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008928:Mitochondria / Q000378:metabolism*; D024101:Mitochondrial Proteins; D008969:Molecular Sequence Data; D009154:Mutation / Q000235:genetics; D010802:Phylogeny; D012441:Saccharomyces cerevisiae / Q000235:genetics / Q000378:metabolism; D029701:Saccharomyces cerevisiae Proteins / Q000235:genetics / Q000378:metabolism; D013234:Stem Cells / Q000166:cytology / Q000378:metabolism; D015027:Zebrafish / Q000235:genetics / Q000378:metabolism; D029961:Zebrafish Proteins / Q000235:genetics / Q000378:metabolism*
D027682:Cation Transport Proteins; D007506:Iron-Sulfur Proteins; C066985:MRS3 protein, S cerevisiae; C066986:MRS4 protein, S cerevisiae; D026901:Membrane Transport Proteins; D024101:Mitochondrial Proteins; D029701:Saccharomyces cerevisiae Proteins; D029961:Zebrafish Proteins; C509051:mitoferrin protein, mouse; C509052:slc25a37 protein, zebrafish; D006418:Heme; D007501:Iron