Functional properties of human ferroportin, a cellular iron exporter reactive also with cobalt and zinc
Open accessAbstract
Iron homeostasis is achieved by regulating the intestinal absorption of the metal and its recycling by macrophages. Iron export from enterocytes or macrophages to blood plasma is thought to be mediated by ferroportin under the control of hepcidin. Although ferroportin was identified over a decade ago, little is understood about how it works. We expressed in Xenopus oocytes a human ferroportin-enhanced green fluorescent protein fusion protein and observed using confocal microscopy its exclusive plasma-membrane localization. As a first step in its characterization, we established an assay to detect functional expression of ferroportin by microinjecting oocytes with 55 Fe and measuring efflux. Ferroportin expression increased the first-order rate constants describing 55 Fe efflux up to 300-fold over control. Ferroportin-mediated 55 Fe efflux was saturable, temperature-dependent (activation energy, E a ≈ 17 kcal/mol), maximal at extracellular pH ≈ 7.5, and inactivated at extracellular pH < 6.0. We estimated that ferroportin reacts with iron at its intracellular aspect with apparent affinity constant < 10 −7 M. Ferroportin expression also stimulated efflux of 65 Zn and 57 Co but not of 64 Cu, 109 Cd, or 54 Mn. Hepcidin treatment of oocytes inhibited efflux of 55 Fe, 65 Zn, and 57 Co. Whereas hepcidin administration in mice resulted in a marked hypoferremia within 4 h, we observed no effect on serum zinc levels in those same animals. We conclude that ferroportin is an iron-preferring cellular metal-efflux transporter with a narrow substrate profile that includes cobalt and zinc. Whereas hepcidin strongly regulated serum iron levels in the mouse, we found no evidence that ferroportin plays an important role in zinc homeostasis.
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The exported species is almost certainly ferrous iron.
“The exported species is almost certainly ferrous iron [12] but the energetics of iron export is not yet well characterized.”
From Hepcidin-Ferroportin Interaction Controls Systemic Iron Homeostasis (2021) · cites this paper as [12]
The smaller ion Mn2+ appears to be transported in liposomes.
“The smaller ion Mn 2+ was previously found not to be effluxed by FPN in oocytes 83 , but appears to be transported in liposomes.”
From Structure of hepcidin-bound ferroportin reveals iron homeostatic mechanisms (2020) · cites this paper as [83]
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“The exported species is almost certainly ferrous iron [12] but the energetics of iron export is not yet well characterized.”
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- Authors
- Mitchell, C. J., Shawki, A., Ganz, T., Nemeth, E., & Mackenzie, B.
- Affiliations
- University of Cincinnati (US)
- University of California, Los Angeles (US)
- Corresponding author
- Mackenzie, Bryan
- Venue
- American Journal of Physiology-Cell Physiology
- Publisher
- American Physiological Society
- Published
- 2014-03-01
- Volume
- 306
- Issue
- 5
- Pages
- C450-C459
- ISSN
- 0363-6143 (ISSN-L)
- 1522-1563
- PMC
- PMC4042619
- OpenAlex
- W2068355995
- Cited by
- 132
- References
- 54
- Citations by year
- 2026: 7 · 2025: 12 · 2024: 7 · 2023: 11 · 2022: 9 · 2021: 8 · 2020: 14 · 2019: 11 · 2018: 16 · 2017: 16 · 2016: 7 · 2015: 9 · 2014: 5
- FWCI
- 5.02
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- American Journal of Physiology-Cell Physiology (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institute of Diabetes and Digestive and Kidney Diseases (R01 DK08271, R01DK080047, P30DK078392)
- David Geffen School of Medicine, University of California, Los Angeles
- Topics
- Health Sciences › Medicine › Hematology › Iron Metabolism and Disorders
- Health Sciences › Nursing › Nutrition and Dietetics › Trace Elements in Health
- Life Sciences › Agricultural and Biological Sciences › Plant Science › Plant Micronutrient Interactions and Effects
- Keywords
- ferroportin, iron efflux, metal transporters, iron homeostasis, hepcidin, zinc efflux, plasma membrane localization, substrate specificity, hypoferremia, zinc homeostasis
- MeSH terms
- Ferroportin, Animals, Biological Transport, Cell Membrane, Cobalt, Homeostasis, Humans, Hydrogen-Ion Concentration, Iron, Kinetics, Male, Mice, Inbred C57BL, Protein Binding, Recombinant Fusion Proteins, Temperature, Xenopus laevis, Zinc, Genes, Reporter, Microscopy, Confocal, Cation Transport Proteins, Green Fluorescent Proteins, Mice, Hepcidins
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