- Review Article
- Open Access
Human iron transporters
© Springer-Verlag 2010
- Received: 20 April 2010
- Accepted: 24 August 2010
- Published: 14 September 2010
Human iron transporters manage iron carefully because tissues need iron for critical functions, but too much iron increases the risk of reactive oxygen species. Iron acquisition occurs in the duodenum via divalent metal transporter (DMT1) and ferroportin. Iron trafficking depends largely on the transferrin cycle. Nevertheless, non-digestive tissues have a variety of other iron transporters that may render DMT1 modestly redundant, and DMT1 levels exceed those needed for the just-mentioned tasks. This review begins to consider why and also describes advances after 2008 that begin to address this challenge.
- Divalent metal transporter (DMT1)
- Ferric reductase
- Iron-responsive element (IRE)
- Iron regulatory protein (IRP)
Because the author recently had the opportunity to address a closely related topic , this review will largely be an update on that one with the emphasis on exploring issues that have arisen since then or were overlooked before or are specific for human iron transporters, again trying to encourage researchers to move to improve our understanding rather than to follow fashion. It will repeat information only where essential for understanding of a topic. New recent relevant reviews include coverage of iron acquisition and storage , impaired iron homeostasis in Parkinsonism , normal iron homeostasis from a molecular viewpoint , normal and pathological iron homeostasis in the eye , hereditary hemochromatosis , hepcidin’s role as a regulator  and recycling of iron primarily by macrophage .
Human cells and tissues manage iron carefully. Nearly all of them need iron to supply redox functions in many pathways in both heme and non-heme proteins. Iron, however, helps to generate reactive oxygen species (ROS) via the same capability, thus the need for careful management.
Earlier, we  called attention to the lack of recent research on a speculative role of mucins interacting with DMT1 in the cellular acquisition of iron from the lumen of the duodenum. A few months later, coculture of cells that model enterocytes with the ones that model goblet (mucin-secreting) cells was described . Such cocultures appear to predict iron bioavailability for foods  and look like a system where new insights can develop. Perhaps they can also encourage a new level of insight into how phytates, polyphenols, and other inhibitors render iron-rich plant foods like spinach into poor sources of iron.
In the previous review , we considered ferritin (ft) in a separate section, but the recent discovery that a form of ft can enter cells via the human TfR1  places ft as an alternative substrate for the Tf cycle. Ft normally consists of 24 subunits of two types called H and L to distinguish the heavier chain from the lighter. The proportion of H and L ft varies. Li et al. show that TfR1 is a receptor also for H ft but not for L ft and that binding leads to H ft entering endosomes and lysosomes. Potentially, H ft can be a source of iron for cells and tissues via this route. The authors clearly distinguish this pathway from that for H ft reliant on T-cell immunoglobulin-domain and mucin-domain protein 2 (TIM-2) in mice [3, 7, 17]. They state that murine TfR1 does not bind human H ft nor murine H ft, suggesting that the mechanism for receptor recognition of H ft diverged between humans and mice. The properties imply that one should look for how well the pathway actually contributes to iron trafficking in human mutants with atransferrinemia or hypotransferrinemia, but that the similar mouse mutants will not be of value in such an appraisal.
Nramp1 (Natural resistance–associated macrophage protein 1) has its highest expression in macrophage as its name implies  and citations therein. There has now been an important advance that helps to define its functions and direction of transport . The investigators showed that loss of either DMT1 or Nramp1 leads to a minor deficit in recycling hemoglobin after erythrophagocytosis. Simultaneous loss of both transporters, however, severely impairs iron recycling. Their work shows that Nramp1 plays a role in the phagosome similar to the one that DMT1 plays in the endosome: Exit of iron toward its destination of recovery for another round of hemoglobin formation. Their data also bear on the controversy on whether Nramp1 is a proton symporter like DMT1 or an antiporter because the function of Nramp1 is now demonstrably partially redundant to DMT1 , implying that Nramp1 is a proton symporter that provides a measure of resistance to many infections by depleting the phagosome of iron and perhaps manganese.
Several aspects of iron transporter properties and regulation in the liver have been covered before  and in citations therein. There is value now in updating two aspects: efforts to modulate transporters and the role of the second Tf receptor (TfR2).
Weiss’s group  have presented data showing that nifedipine, a calcium channel blocker, stimulates DMT1 transport activity. They also reported that nifedipine mobilizes iron from the liver of mice with primary and secondary iron overload and enhances urinary iron excretion. Another result was that nifedipine led to loss of serum iron in a fashion that related to DMT1 genotype in +/+ and +/mk mice where the mk mutation is G185R in DMT1. These results offer nifedipine as a means of modulating iron overload in a fashion that would be off-label use of a USA FDA-approved drug. We  have not been able to reproduce the stimulation of DMT1 by nifedipine and suggest that the ability of photodegraded nifedipine to serve as an iron channel [19, 44, 45] may account for some of their observations. Unfortunately, their statistical analysis  supporting the argument that the DMT1 mutation diminishes the loss of serum iron is flawed and the postulated role of DMT1 in supporting exit of iron would make DMT1 join Fpn as an iron exporter. We do have unpublished data (M. Garrick, L. Zhao, B. Hagerty, S. Gadersohi, A. Ghio, L. Garrick and B. Mackenzie 2009) that suggest that nifedipine treatment does decrease serum iron in rodents in a fashion that does not relate to the DMT1 genotype, so nifedipine could still be of interest for removing iron. Nifedipine’s mechanism for doing so, however, and whether it does diminish liver iron both require more studies.
Although stimulation of DMT1 activity remains elusive, there are multiple reports of potential inhibitors. Ebselen, a seleno compound that may act via redox activity, clearly inhibits DMT1 . Several polysulfonated dyes are also inhibitors .
Most published approaches to Fpn are based on its regulation by hepcidin and other regulators. In this context, the critical involvement of the liver in TfR2 (and HFE) modulation of hepcidin has just been confirmed  in mice. Another study  examines the role of two isoforms of TfR2 mRNA. The α isoform is longer and encodes a full-length TfR2, while the β isoform is shorter. By generating a mouse that lacks the α isoform but retains as a knock-in the β isoform, this group suggests that its product is also involved in regulating Fpn transcription. Their results confirm the already identified function of the α isoform in hepcidin activation but also suggest that β TfR2 is more specifically involved in splenic Fpn function (iron efflux).
Two human iron transporters have two or more isoforms with properties that insure that the isoforms act in different circumstances. These are DMT1 and Fpn.
The 4 isoforms of DMT1 mRNA (1A/+IRE, 1A/−IRE, 1B/+IRE, and 1B/−IRE) also encode related but distinct proteins (Fig. 4b). Potentially, differences between the N-terminus that starts in exon 1A and the one that starts in exon 2 and differences between the 18 C-terminal amino acid residues of the +IRE form and the 25 of the −IRE could affect localization of the transporter within the cell, thus where it functions and even where it turns over. Existing data do suggest the presence of such distinctions [5, 15, 24, 26, 38, 39, 48, 49].
Recently, Rouault’s laboratory  described alternate transcripts for Fpn (Fig. 4c). It is the only known human iron export transporter, as such it regulates the exit of iron from enterocytes into circulation. Their findings resolve a paradox about the regulation of Fpn. Given that the only previously recognized mRNA isoform has an IRE in the 5′ UTR, IRPs binding to that IRE during iron deficiency would shut off synthesis of Fpn, preventing iron absorption when absorption is needed most. Zhang et al. have established that this paradox applies only to one isoform of Fpn mRNA where transcription initiates from its promoter upstream of exon 1a. For some other mRNA isoforms, transcription initiates farther upstream so that the first exon is 1b where splicing to the middle or beyond of exon 1a leads to omission of the IRE. The transcripts that start with exon 1b will then not be down-regulated by iron deficiency. There is a choice of 3 possible splice acceptor sites for the 1a–b splicing, but it is unclear whether this choice has any effect on Fpn gene expression as all 3 lead to Fpn mRNA lacking an IRE. These same transcripts are also well expressed in erythroid differentiation, supporting the postulate  that iron homeostasis in these cells has privileged regulation to handle the heavy demand for iron. The Fpn amino acid sequence predicted by all of the mRNA isoforms is invariant, indicating that the targeting of their products is the same.
Potential and actual human iron transporters
What it does or might do
Divalent metal (ion) transporter
It is the major duodenal importer of ferrous iron and other metal ions; it is also responsible for exit of ferrous iron from endosomes during the Tf cycle; this transporter also participates in Tf-independent iron entry into cells (non-Tf-bound iron uptake) and possibly in transcytosis of iron across enterocytes
Divalent cation transporter
Natural resistance–associated macrophage protein 2
Solute carrier 11a2
It is the only known cellular iron exporter in mammals; this distinction is physiologically important even if the ability of DMT1 to support endosomal iron exit makes it also a semantic point
Metal transporter protein
Solute carrier 40
Natural resistance–associated macrophage protein 1
Identified initially by the phenotype of resistance to many microbial infections, this transporter probably participates in the exit of iron and manganese from phagosomes
It carries ferric iron in the plasma, lymph, and cerebrospinal fluid behaving as an iron transporter in conjunction with TfR1
Tf receptor 1
It binds Tf to deliver iron into cells with the transport process due to receptor-mediated endocytosis
Tf receptor 2
It may also deliver Tf-bound iron and even iron not bound to Tf to some cells
It is primarily an iron storage protein, but H ft may also participate in iron transport by binding to TfR1
Zrt- and Irt-like
Although it was initially identified as a Zn transporter, Zip 14 is responsible for at least a part of iron not bound to Tf uptake in the liver. More speculatively, Zip8 may also be an iron transporter
Ngal 24p3 lipocalin(-2) uterocalin
Neutrophil gelatinase-associated lipocalin
This protein binds iron bound to an internal siderophore that is yet to be identified. It and its receptor are involved in iron withholding during infection and early kidney development
Some Ca channels may also be routes for iron uptake. In addition, there is evidence that the G185R mutation of DMT1 leads to enhanced behavior as a Ca channel for DMT1
Transient receptor potential mucolipidosis–associated protein
Recently shown to act as a channel for iron exit from endosomes and lysosomes, it is best known as a protein in which mutations can cause mucolipidosis type IV disease
It was postulated to be a form of calreticulin but also a major iron transporter, but whether it is or not is not known
I thank Dr. AL Crumbliss for drawing to my attention that it might be more felicitous to what actually happens to consider that Steap3 reduction could occur before release of iron from transferrin. Dr. Laura Garrick carefully read and critiqued multiple versions of this review.
- Andolfo I, De Falco L et al (2010) Regulation of divalent metal transporter 1 (DMT1) non−IRE isoform by the microRNA Let-7d in erythroid cells. Haematologica 95(8):1244–1252Google Scholar
- Beaumont C, Delaby C (2009) Recycling iron in normal and pathological states. Semin Hematol 46(4):328–338View ArticlePubMedGoogle Scholar
- Boddaert N, Le Quan Sang KH et al (2007) Selective iron chelation in Friedreich ataxia: biologic and clinical implications. Blood 110(1):401–408View ArticlePubMedGoogle Scholar
- Buckett PD, Wessling-Resnick M (2009) Small molecule inhibitors of divalent metal transporter-1. Am J Physiol Gastrointest Liver Physiol 296(4):G798–G804View ArticlePubMedGoogle Scholar
- Canonne-Hergaux F, Gruenheid S et al (1999) Cellular and subcellular localization of the Nramp2 iron transporter in the intestinal brush border and regulation by dietary iron. Blood 93(12):4406–4417PubMedGoogle Scholar
- Carlson ES, Tkac I et al (2009) Iron is essential for neuron development and memory function in mouse hippocampus. J Nutr 139(4):672–679View ArticlePubMedGoogle Scholar
- Chen TT, Li L et al (2005) TIM-2 is expressed on B cells and in liver and kidney and is a receptor for H-ferritin endocytosis. J Exp Med 202(7):955–965View ArticlePubMedGoogle Scholar
- De Domenico I, McVey Ward D et al (2008) Regulation of iron acquisition and storage: consequences for iron-linked disorders. Nat Rev Mol Cell Biol 9(1):72–81View ArticlePubMedGoogle Scholar
- Dhungana S, Taboy CH et al (2004) Redox properties of human transferrin bound to its receptor. Biochemistry 43(1):205–209View ArticlePubMedGoogle Scholar
- Fleming MD, Romano MA et al (1998) Nramp2 is mutated in the anemic Belgrade (b) rat: evidence of a role for Nramp2 in endosomal iron transport. Proc Natl Acad Sci USA 95(3):1148–1153View ArticlePubMedGoogle Scholar
- Fleming MD, Trenor CI et al (1997) Microcytic anaemia mice have a mutation in Nramp2, a candidate iron transporter gene. Nature Genet 16(4):383–386PubMedGoogle Scholar
- Foot NJ, Dalton HE et al (2008) Regulation of the divalent metal ion transporter DMT1 and iron homeostasis by a ubiquitin-dependent mechanism involving Ndfips and WWP2. Blood 112(10):4268–4275View ArticlePubMedGoogle Scholar
- Gao J, Chen J et al (2010) Hepatocyte-targeted HFE and TFR2 control hepcidin expression in mice. Blood 115(16):3374–3381Google Scholar
- Garrick MD, Garrick LM (2009) Cellular iron transport. Biochim Biophys Acta Gen Subj 1790(5):309–325View ArticleGoogle Scholar
- Garrick MD, Kuo H-C et al (2006) Comparison of mammalian cell lines expressing distinct isoforms of divalent metal transporter 1 in a tetracycline-regulated fashion. Biochem J 398(3):539–546View ArticlePubMedGoogle Scholar
- Ghio AJ, Turi J et al (2006) Iron homeostasis in the lung. Biol Res 39(a):67–77PubMedGoogle Scholar
- Ghio AJ, Turi JL et al (2007) Lung injury after ozone exposure is iron dependent. Am J Physiol Lung Cell Mol Physiol 292(1):L134–L143View ArticlePubMedGoogle Scholar
- Goralska M, Ferrell J et al (2009) Iron metabolism in the eye: a review. Exp Eye Res 88(2):204–215View ArticlePubMedGoogle Scholar
- Gruen AB, Zhou J et al (2001) Photodegraded nifedipine stimulates uptake and retention of iron in human epidermal keratinocytes. J Investig Dermatol 116(5):774–777View ArticlePubMedGoogle Scholar
- Haeger P, Álvarez Á et al (2010) Increased hippocampal expression of the divalent metal transporter 1 (DMT1) mRNA variants 1B and +IRE and DMT1 protein after NMDA-receptor stimulation or spatial memory training. Neurotox Res 17(3):238–247View ArticlePubMedGoogle Scholar
- Hentze MW, Muckenthaler MU et al (2004) Balancing acts: molecular control of mammalian iron metabolism. Cell 117(3):285–297View ArticlePubMedGoogle Scholar
- Howitt J, Putz U et al (2009) Divalent metal transporter 1 (DMT1) regulation by Ndfip1 prevents metal toxicity in human neurons. Proc Natl Acad Sci 106(36):15489–15494View ArticlePubMedGoogle Scholar
- Hubert N, Hentze MW (2002) Previously uncharacterized isoforms of divalent metal transporter (DMT)-1: implications for regulation and cellular function. Proc Natl Acad Sci USA 99(19):12345–12350View ArticlePubMedGoogle Scholar
- Knöpfel M, Zhao L et al (2005) Transport of divalent transition-metal ions is lost in small-intestinal tissue of b/b Belgrade rats. Biochemistry 44(9):3454–3465View ArticlePubMedGoogle Scholar
- Lall MM, Ferrell J et al (2008) Iron regulates L-cystine uptake and glutathione levels in lens epithelial and retinal pigment epithelial cells by its effect on cytosolic aconitase. Invest Ophthalmol Vis Sci 49(1):310–319View ArticlePubMedGoogle Scholar
- Lam-Yuk-Sung S, Touret N et al (2005) Carboxy-terminus determinants of the iron transporter DMT1/SLC11A2 isoform II (−IRE/1B) mediate internalization from the plasma membrane into recycling endosomes. Biochemistry 44:12149–12159View ArticleGoogle Scholar
- Laparra J, Glahn R et al (2009) Different responses of Fe transporters in Caco-2/HT29-MTX cocultures than in independent Caco-2 cell cultures. Cell Biol Int 33(9):971–977View ArticlePubMedGoogle Scholar
- Lee DW, Andersen JK (2010) Iron elevations in the aging parkinsonian brain: a consequence of impaired iron homeostasis? J Neurochem 112(2):332–339View ArticlePubMedGoogle Scholar
- Lee PL, Gelbart T et al (1998) The human Nramp2 gene: characterization of the gene structure, alternative splicing, promoter region and polymorphisms. Blood Cells Mol Dis 24(9):199–215View ArticlePubMedGoogle Scholar
- Li L, Fang CJ et al (2010) Binding and uptake of H-ferritin are mediated by human transferrin receptor-1. Proc Natl Acad Sci 107(8):3505–3510View ArticlePubMedGoogle Scholar
- Ludwiczek S, Theurl I et al (2007) Ca2+ channel blockers reverse iron overload by a new mechanism via divalent metal transporter-1. Nat Med 13(4):448–454View ArticlePubMedGoogle Scholar
- Ma Y, Yeh M et al (2006) Iron imports. V. Transport of iron through the intestinal epithelium. Am J Physiol Gastrointest Liver Physiol 290:G417–G422View ArticlePubMedGoogle Scholar
- Mackenzie B, Shawki A et al (2010) Calcium-channel blockers do not affect iron transport mediated by divalent metal-ion transporter-1. Blood 115(20):4148–4149Google Scholar
- Mahler GJ, Shuler ML et al (2009) Characterization of Caco-2 and HT29-MTX cocultures in an in vitro digestion/cell culture model used to predict iron bioavailability. J Nutr Biochem 20(7):494–502View ArticlePubMedGoogle Scholar
- McGahan MC, Harned J et al (2005) Iron alters glutamate secretion by regulating cytosolic aconitase activity. Am J Physiol Cell Physiol 288(5):C1117–C1124View ArticlePubMedGoogle Scholar
- Nemeth E, Ganz T (2009) The role of hepcidin in iron metabolism. Acta Haematol 122(2–3):78–86View ArticlePubMedGoogle Scholar
- Núñez MT, Tapia V et al (2010) Iron supply determines apical/basolateral membrane distribution of intestinal iron transporters DMT1 and ferroportin 1. Am J Physiol Cell Physiol 298(3):C477–C485View ArticlePubMedGoogle Scholar
- Paradkar PN, Roth JA (2006) Nitric oxide transcriptionally down-regulates specific isoforms of divalent metal transporter (DMT1) via NF-kappaB. J Neurochem 96(6):1768–1777View ArticlePubMedGoogle Scholar
- Paradkar PN, Roth JA (2006) Post-translational and transcriptional regulation of DMT1 during P19 embryonic carcinoma cell differentiation by retinoic acid. Biochem J 394(1):173–183View ArticlePubMedGoogle Scholar
- Ponka P (1997) Tissue-specific regulation of iron metabolism and heme synthesis: distinct control mechanisms in erythroid cells. Blood 89(1):1–25PubMedGoogle Scholar
- Roetto A, Di Cunto F et al (2010) Comparison of three Tfr2-deficient murine models suggests distinct functions for TFR2 alpha and beta isoforms in different tissues. Blood 115(16):3382–3389Google Scholar
- Roth JA, Singleton S et al (2010) Parkin regulates metal transport via proteasomal degradation of the 1B isoforms of divalent metal transporter 1. J Neurochem 113(2):454–464View ArticlePubMedGoogle Scholar
- Salazar J, Mena N et al (2008) Divalent metal transporter 1 (DMT1) contributes to neurodegeneration in animal models of parkinson’s disease. Proc Natl Acad Sci 105(47):18578–18583View ArticlePubMedGoogle Scholar
- Savigni DL, Morgan EH (1996) Mediation of iron uptake and release in erythroid cells by photodegradation products of nifedipine. Biochem Pharmacol 51(12):1701–1709View ArticlePubMedGoogle Scholar
- Savigni DL, Wege D et al (2003) Iron and transition metal transport into erythrocytes mediated by nifedipine degradation products and related compounds. Biochem Pharmacol 65(8):1215–1226View ArticlePubMedGoogle Scholar
- Sharp P, Tandy S et al (2002) Rapid regulation of divalent metal transporter (DMT1) protein but not mRNA expression by non-haem iron in human intestinal Caco-2 cells. FEBS Lett 510(1–2):71–76View ArticlePubMedGoogle Scholar
- Soe-Lin S, Apte SS et al (2010) Both Nramp1 and DMT1 are necessary for efficient macrophage iron recycling. Exp Hematol 38(8):609–617Google Scholar
- Tabuchi M, Tanaka N et al (2002) Alternative splicing regulates the subcellular localization of divalent metal transporter 1 isoforms. Mol Biol Cell 13:4371–4387View ArticlePubMedGoogle Scholar
- Tabuchi M, Yanatori I et al (2010) Retromer-mediated direct sorting is required for proper endosomal recycling of the mammalian iron transporter DMT1. J Cell Sci 123(5):756–766View ArticlePubMedGoogle Scholar
- Tchernitchko D, Bourgeois M et al (2002) Expression of the two mRNA isoforms of the iron transporter Nramp2/DMTI in mice and function of the iron responsive element. Biochem J 363(3):449–455View ArticlePubMedGoogle Scholar
- Wareing M, Ferguson CJ et al (2000) In vivo characterization of renal iron transport in the anaesthetized rat. J. Physiol (Lond.) 524(2): 581–586Google Scholar
- Weiss G (2010) Genetic mechanisms and modifying factors in hereditary hemochromatosis. Nat Rev Gastroenterol Hepatol 7(1):50–58View ArticlePubMedGoogle Scholar
- Wetli HA, Buckett PD et al (2006) Small-molecule screening identifies the selanazal drug ebselen as a potent inhibitor of DMT1-mediated iron uptake. Chem Biol 13(9):965–972View ArticlePubMedGoogle Scholar
- Wheby MS, Jones LG et al (1964) Studies on iron absorption. Intestinal regulatory mechanisms. J Clin Invest 43(7):1433–1442View ArticlePubMedGoogle Scholar
- Zecca L, Youdim M et al (2004) Iron, brain ageing and neurodegenerative disorders. Nat Rev Neurosci 5(11):863–873View ArticlePubMedGoogle Scholar
- Zhang A, Enns C (2009) Molecular mechanisms of normal iron homeostasis. Hematol Am Soc Hematol Educ Progr 2009:207–214Google Scholar
- Zhang D-L, Hughes RM et al (2009) A ferroportin transcript that lacks an iron-responsive element enables duodenal and erythroid precursor cells to evade translational repression. Cell Metab 9(5):461–473View ArticlePubMedGoogle Scholar