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Mitoferrin is essential for erythroid iron assimilation
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 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.
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“For example, SLC25A37 encodes mitoferrin-1, an important iron introducer for the synthesis of heme and iron–sulfur clusters in erythroblast mitochondria”
From Red Blood Cells as Potential Repositories of MicroRNAs in the Circulatory System (2020) · cites this paper as Shaw et al., 2006
In the citing paper
“The mitoferrin transporters (Mitoferrin1 and Mitoferrin2) are responsible for the mitochondrial import of iron (Shaw et al., 2006; Troadec et al., 2011; Chung et al., 2014).”
From The Role of Iron Regulation in Immunometabolism and Immune-Related Disease (2019) · cites this paper as Shaw et al., 2006
In the citing paper
“Mitoferrin was originally discovered in yeast (called MRS3/MRS4 16 ) and in a mutant zebrafish.17”
From Forging a field: the golden age of iron biology. (2008) · cites this paper as [17]
In the citing paper
“Interestingly, mutations in mitoferrin result in a clinical disorder that is very similar to erythropoietic protoporphyria caused by ferrochelatase mutations.17”
From Forging a field: the golden age of iron biology. (2008) · cites this paper as [17]
In the citing paper
“The mitochondrial iron importer was recently identified as mitoferrin (also known as SLC25A37), a transmembrane protein that plays a critical role in supplying iron to ferrochelatase for insertion into protoporphyrin IX.”
From Forging a field: the golden age of iron biology. (2008) · cites this paper as [17]
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Self-citation
Metadata
- Authors
- Shaw, G. C., Cope, J. J., Li, L., Corson, K., Hersey, C., Ackermann, G. E., Gwynn, B., Lambert, A. J., Wingert, R. A., Traver, D., Trede, N. S., Barut, B. A., Zhou, Y., Minet, E., Donovan, A., Brownlie, A., Balzan, R., Weiss, M. J., Peters, L. L., Kaplan, J., Zon, L. I., & Paw, B. H.
- Affiliations
- Brigham and Women's Hospital (US)
- University of Utah (US)
- Boston Children's Hospital (US)
- Jackson Laboratory (US)
- University of Malta (MT)
- Children's Hospital of Philadelphia (US)
- Corresponding author
- Paw, Barry H.
- ORCID
- Venue
- Nature
- Published
- 2006-03
- Volume
- 440
- Issue
- 7080
- Pages
- 96-100
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- OpenAlex
- W1972998779
- Cited by
- 624
- References
- 30
- Citations by year
- 2026: 23 · 2025: 32 · 2024: 40 · 2023: 29 · 2022: 24 · 2021: 38 · 2020: 56 · 2019: 26 · 2018: 24 · 2017: 29 · 2016: 30 · 2015: 27 · 2014: 32 · 2013: 28 · 2012: 30
- FWCI
- 16.48
- Type
- journal article
- Language
- en
- Open access
- closed
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature (publishedVersion)
- PubMed (publishedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- The Mouseion at the JAXlibrary (Jackson Laboratory) (submittedVersion)
- Funders
- National Heart, Lung, and Blood Institute (P01HL032262, R01HL075714)
- National Institute of Diabetes and Digestive and Kidney Diseases (R01DK070838)
- Topics
- Health Sciences › Medicine › Hematology › Iron Metabolism and Disorders
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Mitochondrial Function and Pathology
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Biochemistry › Hemoglobin structure and function
- Keywords
- heme biosynthesis, erythroblasts, erythroid maturation, hypochromic anemia, SLC25A37, iron-sulfur cluster assembly, iron homeostasis, positional cloning
- MeSH terms
- Anemia, Animals, Cell Differentiation, Erythroblasts, Gene Expression Regulation, Genetic Complementation Test, Heme, Homeostasis, Humans, Iron, Iron-Sulfur Proteins, Mitochondria, Molecular Sequence Data, Mutation, Phylogeny, Saccharomyces cerevisiae, Stem Cells, Zebrafish, Conserved Sequence, Iron Overload, Mitochondrial Proteins, Membrane Transport Proteins, Cation Transport Proteins, Saccharomyces cerevisiae Proteins, Zebrafish Proteins, Mice
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