Targeted gene disruption reveals an essential role for ceruloplasmin in cellular iron efflux

Harris, Z. Leah; Durley, Alison P.; Man, Tsz-Kwong; Gitlin, Jonathan D.

doi:10.1073/pnas.96.19.10812

Cited by 529 publications

(410 citation statements)

References 37 publications

(43 reference statements)

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“…Macrophages, like other cells, store iron in ferritin. Iron eventually is exported to plasma transferrin by ferroportin with the aid of the multicopper ferroxidase ceruloplasmin (9), but it remains to be established whether ceruloplasmin interacts directly with ferroportin. Ceruloplasmin-deficient patients have a mild impairment of iron mobilization from macrophages as indicated by a mild anemia and gradual iron retention in macrophages, suggesting that the ferroxidase function of ceruloplasmin is partially redundant.…”

Section: Iron Recycling and Storagementioning

confidence: 99%

Molecular Control of Iron Transport

Ganz

2007

Journal of the American Society of Nephrology

320

225

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The iron-regulatory hormone hepcidin is a 25-amino acid peptide that is synthesized in hepatocytes. Hepcidin binds to the cellular iron export channel ferroportin and causes its internalization and degradation and thereby decreases iron efflux from iron exporting tissues into plasma. By this mechanism, hepcidin inhibits dietary iron absorption, the efflux of recycled iron from splenic and hepatic macrophages, and the release of iron from storage in hepatocytes. Hepcidin synthesis is stimulated by plasma iron and iron stores and is inhibited by erythropoietic activity, ensuring that extracellular plasma iron concentrations and iron stores remain stable and the erythropoietic demand for iron is met. During inflammation, increased hepcidin concentrations cause iron sequestration in macrophages, resulting in hypoferremia and eventually anemia of inflammation. Hepcidin deficiency plays a central role in most iron overload disorders. The role of hepcidin abnormalities in anemias that are associated with renal disease and in resistance to erythropoietic therapies remains to be elucidated.

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Section: Iron Recycling and Storagementioning

confidence: 99%

Molecular Control of Iron Transport

Ganz

2007

Journal of the American Society of Nephrology

320

225

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“…A fraction of the reduced iron may be oxidized and securely sequestered in ferritin. Alternatively, iron may be transferred across the basolateral membrane by ferroportin (3)(4)(5), where it is oxidized to the ferric state by the membrane-bound multi-copper ferroxidase hephaestin or the homologous soluble ferroxidase ceruloplasmin (6,7). Oxidized iron is then loaded onto transferrin (TF), 2 a soluble protein in the blood that securely transports and distributes iron to downstream tissues.…”

Section: General Iron Homeostasismentioning

confidence: 99%

Regulation of Iron Metabolism by Hepcidin under Conditions of Inflammation

Schmidt

2015

Journal of Biological Chemistry

136

105

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Iron is a redox-active metal required as a cofactor in multiple metalloproteins essential for a host of life processes. The metal is highly toxic when present in excess and must be strictly regulated to prevent tissue and organ damage. Hepcidin, a molecule first characterized as an antimicrobial peptide, plays a critical role in the regulation of iron homeostasis. Multiple stimuli positively influence the expression of hepcidin, including iron, inflammation, and infection by pathogens. In this Minireview, I will discuss how inflammation regulates hepcidin transcription, allowing for sufficient concentrations of iron for organismal needs while sequestering the metal from infectious pathogens.Iron is crucial for many life functions in both eukaryotic hosts and prokaryotic pathogens. Due to its ability to readily accept or donate electrons, iron is a valuable cofactor in proteins essential in metabolic processes. However, when left unsupervised, iron can also react with oxygen to generate radical oxygen species that can damage all facets of a cell, leading to tissue damage and eventual organ failure. Therefore, it is crucial for organisms to maintain strict control over iron uptake and distribution to assure appropriate amounts for life requirements, yet regulate and sequester it tightly to prevent oxidative stress or microbial proliferation during infection. Herein, I will present an overview of how iron balance is maintained in vertebrate organisms and discuss the role of hepcidin, the master regulator of iron metabolism, in iron regulation during inflammation and infection. General Iron HomeostasisEach day the average human must absorb 1-2 mg of iron from the diet to offset unregulated losses from general bleeding, menstruation, or the sloughing of epithelial cells. Iron is a critical cofactor required for DNA synthesis, mitochondrial respiration, and various signaling pathways. Most crucially, almost 25 mg of iron per day is required for hemoglobin synthesis and the replacement of an estimated 200 billion RBCs. The vast majority of this iron pool is acquired through the recycling of senescent erythrocytes by macrophages of the reticuloendothelial compartment. Whole body iron homeostasis is thought to occur completely at the level of iron absorption, as no physiologically regulated means of iron excretion has been elucidated. Hence, influx of iron from the diet, and recycling of iron from aged or damaged RBCs, must be closely regulated to prevent iron-restricted erythropoiesis resulting in anemia or excess iron loading and subsequent tissue damage caused by the generation of radical oxygen species. Proper distribution of circulating iron to tissues such as the brain, heart, and skeletal muscle is crucial for the prevention of human disease states.Non-heme dietary reduced iron is admitted into the body through divalent metal transporter 1 (DMT1, Slc11a2) (1, 2), an iron transporter located on the apical membrane of duodenal enterocytes located in the first section of the small intestine ( Fig. 1). After uptake in...

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“…Its apparent role in Fe transport (attributed to its ferroxidase activity) has been of particular recent interest. Thus, in humans (Harris et al 1998;Harris et al 1995;Yoshida et al 1995) or mice (Harris et al 1999) lacking ceruloplasmin genetically or through severe Cu deficiency (Linder 1991;Linder 2002;Osaki & Johnson 1969;Ragan et al 1969) there is a gradual accumulation of excess iron in certain tissues, including the liver and retina, resulting in tissue damage. This has been explained on the basis that ceruloplasmin oxidizes Fe(II) as it leaves cellular storage sites, promoting the binding of the resulting Fe(III) to its blood plasma transporter, transferrin (Frieden 1970;Linder 1991).…”

Section: Introductionmentioning

confidence: 99%

Copper binding components of blood plasma and organs, and their responses to influx of large doses of 65Cu, in the mouse

et al. 2008

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To establish for the first time how mice might differ from rats and humans in terms of copper transport, excretion, and copper binding proteins, plasma and organ cytosols from adult female C57CL6 mice were fractionated and analyzed by directly coupled size exclusion HPLC-ICP-MS, before and after i.p. injection of large doses of 65 Cu. Plasma from untreated mice had different proportions of Cu associated with transcuprein/macroglobulin, ceruloplasmin and albumin than in humans and rats, and two previously undetected copper peaks (Mr 700k and 15k) were observed. Cytosols had Cu peaks seen previously in rat liver (Mr >1000k, 45k and 11k) plus one of 110kDa. 65 Cu (141 μg) administered over 14h, initially loaded plasma albumin and mainly entered liver and kidney (especially 28kDa and 11kDa components). Components of other organs were less, but still significantly enriched. 63 Cu/ 65 Cu ratios returned almost to normal by 14d, indicating a robust system for excreting excess copper. We conclude that there are significant differences but also strong similarities in copper metabolism between mice, rats and humans; that the liver is able to buffer enormous changes in copper status; and that a large number of mammalian copper proteins remain to be identified.

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Targeted gene disruption reveals an essential role for ceruloplasmin in cellular iron efflux

Abstract: Aceruloplasminemia is an autosomal recessive disorder of iron metabolism. Affected individuals evidence iron accumulation in tissue parenchyma in association with absent serum ceruloplasmin. Genetic studies of such patients reveal inherited mutations in the ceruloplasmin gene.

Cited by 529 publications

References 37 publications

Molecular Control of Iron Transport

Molecular Control of Iron Transport

Regulation of Iron Metabolism by Hepcidin under Conditions of Inflammation

Copper binding components of blood plasma and organs, and their responses to influx of large doses of 65Cu, in the mouse

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