Regulation of mammalian iron homeostasis

Current Opinion in Clinical Nutrition and Metabolic Care

Volumn 3, Issue 4, 2000, Pages 267-273

  Schneider, Brian D ^a   Leibold, Elizabeth A ^a,b  

^a UNIVERSITY OF UTAH SCHOOL OF MEDICINE   (United States)

^b UNIVERSITY OF UTAH   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

BODY BURDEN; ERYTHROPOIESIS; HOMEOSTASIS; HUMAN; IRON METABOLISM; IRON TRANSPORT; MAMMAL; METABOLIC REGULATION; NONHUMAN; OXIDATION REDUCTION STATE; REVIEW;

ANIMALS; ANOXIA; HOMEOSTASIS; HUMANS; INTESTINAL ABSORPTION; IRON; IRON-REGULATORY PROTEINS; IRON-SULFUR PROTEINS; OXIDATIVE STRESS; RESPONSE ELEMENTS; RNA; RNA-BINDING PROTEINS;

MAMMALIA;

EID: 0033913493     PISSN: 13631950     EISSN: None     Source Type: Journal    
DOI: 10.1097/00075197-200007000-00005     Document Type: Review

References (56)

1. Andrews NC, Fleming MD, Gunshin H. Iron transport across biologic membranes. Nutr Rev 1999; 57:114-123.
2. Riedel H-D, Remus AJ, Fitscher BA, Stremmel W. Characterization and partial purification of a ferrireductase from human duodenal microvillus membranes. Biochem J. 1995; 309:745-748.
3. Gunshin H, Mackenzie B, Berger U, et al. Cloning and characterization of a mammalian proton-coupled metal-ion transporter. Nature 1997; 388:482-488.
4. Lee PL, Gelbart T, West C, et al. The human Nramp2 gene: characterization of the gene structure, alternative splicing, promoter region and polymorphisms. Blood Cells Mol Dis 1998; 24:199-215.
5. Fleming RE, Migas MC, Zhou X, et al. Mechanism of increased iron absorption • in murine model of hereditary hemochromatosis: increased duodenal expression of the iron transporter DMT1. Proc Natl Acad Sci USA 1999; 96:13143-13148. Fleming et al, demonstrated that the IRE form of DMT1 messenger RNA is upregulated in the duodenum of iron-deficient mice and in HFE-null mice, supporting the notion that HFE mutation leads to iron-deficient crypt cells and increased iron uptake.
6. Canonne-Hergaux F, Gruenheid S, Ponka P, Gros P. Cellular and subcellular •• localization of the Nramp2 iron transporter in the intestinal brush border and regulation by dietary iron. Blood 1999; 12:4406-4417. The authors provide a detailed analysis of the cellular and subcellular localization of DMT1 protein in tissues from normal and iron-deficient mice.
7. Fleming MD, Romano MA, Su MA, et al. Nramp2 is mutated in the anemic Belgrade (b) rat: evidence of a role for Nramp2 in endosomal iron transport. Proc Natl Acad Sci USA 1998; 95:1148-1153.
8. Fleming MD, Trenor CCr, Su MA, et al. Microcytic anaemia mice have a mutation in Nramp2, a candidate iron transporter gene. Nature Genet 1997; 4:383-386.
9. Su MA, Trenor CC, Fleming JC, et al. The G185R mutation disrupts function of the iron transporter Nramp2. Blood 1998; 92:2157-2163.
10. Conrad ME, Umbreit JN, Moore EG. Iron absorption and transport. Am J Med Sci 1999; 8:213-229.
11. Donovan A, Brownlie A, Shepard J, et al. Zebrafish weissherbst encodes •• ferroportin-1, a gene required for iron transport during embryogenesis. Nature 2000; 403:776-781. The authors used positional cloning to identify the zebrafish gene (which encodes ferroportin-1) that is defective in weh mutants. Further studies showed that ferroportin-1 is localized to the basolateral membranes in human duodenal enterocytes and placental synctiotrophoblasts, and is presumed to be the elusive basolateral intestinal iron transporter in mammals. Zebrafish ferroportin-1 is the ortholog of mammalian Ireg1.
12. McKie A, Marcani P, Rolfs A, et al. A novel duodenal iron-regulated membrane •• protein (Ireg1) implicated in the basolateral transfer of iron to the circulation. Molecular Cell 2000; 5:229-303. This article describes the long-awaited cloning of the mammalian intestinal basolateral iron transporter Ireg1. This paper also shows that Ireg1 is localized to the basolateral membrane of epithelial cells and that Ireg1 facilitates iron efflux when expressed in Xenopus laevis oocytes, supporting a role for Ireg1 in the transfer of iron to the circulation.
13. Vulpe CD, Kuo YM, Murphy TL, et al. Hephaestin, a ceruloplasmin homologue •• implicated in intestinal iron transport is defective in the s/a mouse. Nature Genet 1999; 2:195-199. This paper identifies the genetic defect in s/a mice as hephaestin, a ceruloplasmin homolog. Hephaestin has been implicated in facilitating iron efflux from duodenal cells and may function in concert with Ireg1/ferroportin-1 in iron release from enterocytes.
14. Harris ZL, Durley AP. Man TK, Gitlin JD. Targeted gene disruption reveals an •• essential role for ceruloplasmin in cellular iron efflux. Proc Natl Acad Sci USA 1999; 96:10812-10817. This paper describes the phenotype of ceruloplasmin-null mice and shows that ceruloplasmin is essential in the mobilization of iron from reticuloendothelial cells and hepatocytes.
15. Yu J, Wessling-Resnick M. Structural and functional analysis of SFT, a stimulator of iron transport. J Biol Chem 1998; 273:21380-21385.
16. Yu J, Yu ZK, Wessling-Resnick M. Expression of SFT (stimulator of Fe transport) is enhanced by iron chelation in HeLa cells and by hemochromatosis in liver. J Biol Chem 1998; 273:34675-34678.
17. Feder JN. The hereditary hemochromatosis gene (HFE). Immunol Res 1999; 20:175-185.
18. Olynyk JK, Cullen D, Aquilia S, et al. A population-based study of the clinical • expression of the hemochromatosis gene. N Eng J Med 1999; 341:718-724. The authors used a population-based study to assess the prevalence and clinical expression of the HFE gene, and showed that only half of the patients who are homozygous for the HFE mutation have clinical features of hemochromatosis.
19. 2-microglobulin interaction and cell surface expression. J Biol Chem 1997; 272:14025-14028.
20. Lebron JA, Bennett MJ, Vaughn DE, et al. Crystal structure of the hemochromatosis protein HFE and characterization of its interaction with transferrin receptor. Cell 1998; 93:111-123.
21. 2-microglobulin, intracellular processing, and cell surface expression of the HFE protein in COS-7 cells. Proc Natl Acad Sci USA 1997; 94:12384-12389.
22. Levy JE, Montross KL, Cohen DE, et al. The C282Y mutation causing hereditary • hemochromatosis does not produce a null allele. Blood 1999; 94:9-11. This paper describes the generation of a mouse carrying the hemochromatosis C282Y mutation and provides data that show that this mutation does not produce a null allele.
23. Zhou X, Tomatsu S, Fleming RE, et al. HFE gene knockout produces mouse model of hereditary hemochromatosis. Proc Natl Acad Sci USA 1998; 95:2492-2497.
24. 2 Knockout mice develop parenchymal iron overload: a putative role for class I genes of the major histocompatibility complex in iron metabolism. Proc Natl Acad Sci USA 1996; 93:1529-1534.
25. Parkkila S, Waheed A, Britton RS, et al. Immunohistochemistry of HLA-H, the protein defective in patients with hereditary hemochromatosis, reveals unique pattern of expression in gastrointestinal tract. Proc Natl Acad Sci USA 1997; 94:2534-2539.
26. Waheed A, Parkkila S, Saarnio J, et al. Association of HFE protein with • transferrin receptor in crypt enterocytes of human duodenum. Proc Natl Acad Sci USA 1999; 96:1579-1584. The authors show that both TfR and HFE are physically associated in the crypt enterocyte, and that crypt cells show higher transferrin-iron uptake than villus cells, supporting the proposal that HFE modulates uptake of plasma transferrin.
27. Gross CN, Irrinki A, Feder JN, Enns CA. Co-trafficking of HFE, a nonclassical major histocompatibility complex class I protein, with the transferrin receptor implies a role in intracellular iron regulation. J Biol Chem 1998; 273:22068-22074.
28. Bennett M, Lebron JA, Bjorkman PJ. Crystal structure of the hereditary •• haemochromatosis protein HFE complexed with transferrin receptor. Nature 2000; 403:46-53. This paper describes the 2.8-crystal structure of HFE complexed with the TfR.
29. Feder JN, Penny DM, Irrinki A, et al. The hemochromatosis gene product complexes with the transferrin receptor and lowers its affinity for ligand binding. Proc Natl Acad Sci USA 1998; 95:1472-1477.
30. Lebron JA, West APJ, Bjorkman PJ. The hemochromatosis protein HFE • competes with transferrin for binding to the transferrin receptor. J Mol Biol 1999; 294:239-245. The authors provide a detailed analysis of the interaction of the TfR with transferrin-iron and with HFE using radioactivity-based and biosensor-based assays.
31. Roy CN, Penny DM, Feder JN, Enns CA. The hereditary hemochromatosis •• protein, HFE, specifically regulates transferrin-mediated iron uptake in HeLa cells. J Biol Chem 1999; 274:9022-9028. This paper provides data in support of the model that HFE reduce the cellular acquisition of iron from transferrin in the endosome.
32. Riedel HD, Muckenthaler MU, Gehrke SG, et al. HFE downregulates iron • uptake from transferrin and induces iron-regulatory protein activity in stably transfected cells. Blood 1999; 94:3915-3921. Overexpression of HFE in cultured cells activates IRP RNA-binding activity and downregulates transferrin iron uptake, suggesting that HFE affects the intracellular iron pool.
33. Cairo G, Recalcati S, Montosi G, et al. Inappropriately high iron regulatory protein activity in monocytes of patients with genetic hemochromatosis. Blood 1997; 89:2546-2553.
34. Salter-Cid L, Brunmark A, Li Y, et al. Transferrin receptor is negatively • modulated by the hemochromatosis protein HFE: implications for cellular iron homeostasis. Proc Natl Acad Sci USA 1999; 96:5434-5439. The authors show that HFE binding to TfR reduces the number of surface TfRs for binding to transferrin and impairs TfR internalization, resulting in decreased uptake of transferrin-bound iron.
35. Zoller H, Pietrangelo A, Vogel W, Weiss G. Duodenal metal-transporter (DMT1, • NRAMP-2) expression in patients with hereditary hemochromatosis. Lancet 1999; 353:2120-2123. DMT1 messenger RNA expression is increased in duodenal mucosa of patients with hemochromatosis, implying that increased DMT1 expression may promote duodenal iron uptake and iron overload.
36. Aisen P, Wessling-Resnick, M, Leibold EA. Iron metabolism. Curr Opin Chem Biol 1999; 3:200-206.
37. Kaldy P, Menotti E, Moret R, Kuhn LC. Identification of RNA-binding surfaces in • iron regulatory protein-1. EMBO J 1999; 18:6073-6083. Site-directed mutagenesis of IRP1 that shows specific regions involved in RNA-binding and recognition. Direct interaction between the IRE and specific residues will require a crystal structure of the complex.
38. Gegout V, Schlegl J, Schlager B, et al. Ligand-induced structural alterations in • human iron regulatory protein-1 revealed by protein footprinting. J Biol Chem 1999; 274:15052-15058. This paper presents evidence to support the model of suggesting structural changes associated with conversion of IRP1 from RNA-binding to [4Fe-4S] cluster form.
39. Iwai K, Drake SK, Wehr NB, et al. Iron-dependent oxidation, ubiquitination, and degradation of iron regulatory protein 2: implications for degradation of oxidized proteins. Proc Natl Acad Sci USA 1998; 95:4924-4928.
40. Kim S, Ponka P. Control of transferrin receptor expression via nitric oxide-•• mediated modulation of iron-regulatory protein 2. J Biol Chem 1999; 274:33035-33042. A clear demonstration is provided that different redox forms of NO can differentially affect IRP binding activity and function. Additional data is presented to support a model of NO activating IRP1 RNA-binding via direct interaction with the [4Fe-4S] cluster.
41. Brazzolotto X, Gaillard J, Pantopoulos K, et al. Human cytoplasmic aconitase is • converted into its [3Fe-4S] form by hydrogen peroxide in vitro but is not activated for iron-responsive element binding. J Biol Chem 1999; 274:21625-21630. The authors present data that suggest that hydrogen peroxide may not be as destructive to the [4Fe-4S] cluster as initially thought.
42. 2) control mammalian iron metabolism by different pathways. Mol Cell Biol 1996; 16:3781-3788.
43. Oliveira L, Bouton C, Drapier JC. Thioredoxin activation of iron regulatory • proteins: redox regulation of RNA binding after exposure to nitric oxide. J Biol Chem 1999; 274:516-521. This paper demonstrates how a major physiological reducing agent can modulate IRP activity in the presence of NO. A mechanism for the activation of oxidized apo-IRP1 is also proposed.
44. Pantopoulos K, Hentze MW. Activation of iron regulatory protein-1 by oxidative stress in vitro. Proc Natl Acad Sci USA 1998; 95:10559-10563.
45. Gehring NH, Hentze MW, Pantopoulos K. Inactivation of both RNA-binding and •• aconitase activities of iron regulatory protein 1 by quinone-induced oxidative stress. J Biol Chem 1999; 274:6219-6225. The interesting observation is made that both functions of IRP1 are inactivated following a specific oxidative stress. Curiously, the data suggest that this is not due to IRP1 degradation, although ferritin translation is inhibited.
46. Kispal G, Csere P, Prohl C, Lill R. The mitochondrial proteins Atm1p and Nfs1p •• are essential for biogenesis of cytosolic Fe/S proteins. EMBO J 1999; 18:3981-3989. This study demonstrates the role of two mitochondrial proteins in the biogenesis of Fe-S proteins using a newly developed immunoprecipitation procedure. Such work has important implications in the regulation of iron uptake and a number of iron-related disorders.
47. Li J, Kogan M, Knight SAB, et al. Yeast mitochondrial protein, Nfs1p, • coordinately regulates iron-sulfur cluster proteins, cellular iron uptake, and iron distribution. J Biol Chem 1999; 274:33025-33034. This study shows that Nfs1p also regulates cellular iron homeostasis via iron uptake and distribution, in addition to its role in Fe-S cluster assembly.
48. Lange H, Kaut A, Kispal G, Lill R. A mitochondrial ferredoxin is essential for •• biogenesis of cellular iron-sulfur proteins. Proc Natl Acad Sci USA 2000; 97:1050-1055. This paper identifies a mitochondrial ferredoxin that is required for the assembly of both mitochondrial and cytoplasmic Fe-S proteins in yeast, providing further support for a role of mitochondria in Fe-S cluster assembly.
49. Pantopoulos K, Mueller S, Atzberger A, et al. Differences in the regulation of iron regulatory protein-1 (IRP-1) by extra-and intracellular oxidative stress. J Biol Chem 1997; 272:9802-9808.
50. Hanson ES, Leibold EA. Regulation of iron-regulatory proteins by reactive nitrogen and oxygen species. Gene Expression 1999; 7:367-376.
51. Hanson ES, Foot LS, Leibold EA. Hypoxia post-translationally activates iron-•• regulatory protein 2. J Biol Chem 1999; 274:5047-5052. This paper shows the differential regulation of IRP1 and IRP2 during hypoxia. In addition, unique parallels are drawn between the hypoxia-induced activation of IRP2 and hypoxia-inducible factor 1α (HIF-α), suggesting similar mechanisms of regulation.
52. Beaumont C, Leneuve P, Devaux I, et al. Mutation in the iron responsive element of the L ferritin mRNA in a family with dominant hyperferritinemia and cataract. Nature Genet 1995; 11:444-446.
53. Rouault TA, LaVaute T, Smith S, et al. The role of CNS iron accumulation in a progressive neurodegenerative disease of mice. In: First International Workshop on Iron and Copper Homeostasis, Pucon, Chile, Nov 25, 1999; page 2 [abstract].
54. Ke Y, Wu J, Leibold EA, et al. Loops and bulge/loops in iron-responsive element isoforms influence iron regulatory protein binding: fine-tuning of mRNA regulation? J Biol Chem 1998; 273:23637-23640.
55. Shimada Y, Okuno S, Kawai A, et al. Cloning and chromosomal mapping of a novel ABC transporter gene (hABC7), a candidate for X-linked sideroblastic anemia with spinocerebellar ataxia. J Hum Genet 1998; 43:115-122.
56. Allikmets R, Raskind WH, Hutchinson A, et al. Mutation of a putative • mitochondrial iron transporter gene (ABC7) in X-linked sideroblastic anemia and ataxia (XLSA/A). Hum Mol Genet 1999; 8:743-749 This study provides evidence to indicate that a mutation in the mitochondrial iron transporter ABC7 is responsible for X-linked sideroblastic anemia and ataxia.