1. ABSORPTION REGULATION RECYCLING TRANSPORT STORAGE USAGE LOSS
Iron Metabolism
ABSORPTION
REGULATION
~ 300 mg
1-2 mg/d
25 mg/d
3 mg
~ 1000 mg
~ 600 mg
~ 1800 mg
Total body iron mg
RECYCLING
TRANSPORT
STORAGE
USAGE
LOSS
These presentations are part of the IronAtlas. Usage of the IronAtlas is subject to the Terms of Use ( © 2015 Vifor Pharma. All rights reserved.
Reproduction, publication or distribution (in full or in part) is only permitted with the prior written consent of Vifor Pharma.
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Further information:
Contact:
Design: descience - A. Ulrich & N. Stadelmann, Lucerne
Realisation IronAtlas: Monokel Games GmbH, Zurich
Project management: Dr. Pascal Schär & Dr. Viktor Pavelic, Vifor Pharma
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Non-commercial use permitted for training purposes in unaltered form with indication of source.

2. Iron Metabolism - Absorption
DMT-1
Dcytb
Transferrin
Hephaestin
Ferroportin
HCP-1
Ferritin
Fe(III)
Fe(II)
Haem iron
Apotransferrin 1 2 3 4 5 6 7 8
ENTEROCYTE
APICAL
BASOLATERAL
The first step in the intestinal absorption of iron from food takes place on the apical side of the enterocytes in the duodenum and upper jejunum. Each of the various forms that iron can take in food (Fe(II), Fe(III) or haem iron) has a specific absorption mechanism (DMT1, Dcytb and HCP, respectively). Iron absorption is only complete once the iron has passed into the circulation basolaterally via ferroportin. The individual mechanisms are strictly regulated in order to ensure iron homeostasis.
1) Dietary iron
Iron is absorbed from food in the intestinal lumen by the enterocytes in the duodenum. There are three transport mechanisms for absorbing trivalent iron (Fe(III), mainly plant-based), divalent iron (Fe(II), reduced form of iron) or iron bound to a haem group (haem iron, mainly animal-based) from food.
2) Conversion of Fe(III) into Fe(II) via Dcytb
The apical reduction of Fe(III) to Fe(II) takes place via the ferric reductase duodenal cytochrome B (Dcytb).
3) Absorption of Fe(II) via DMT1
Fe(II) is absorbed from the intestinal lumen into the enterocytes via divalent metal transporter 1 (DMT1).
4) AufAbsorption of haem iron via HCP1
Haem iron is absorbed from the intestinal lumen into the enterocytes by haem carrier protein 1 (HCP1).
5) Intracellular transport
Within cells, iron is found in the labile iron pool (LIP). Bound to chelators, it is redox active and involved in many biological processes.
Cave: If iron is bound to ferritin in the enterocytes, it is lost in the desquamation of the intestines (enterocyte life expectancy: 1–2 days).
6) BasoBasolateral export via ferroportin
Iron enters the circulation from the enterocytes via ferroportin. Only once this step is complete is iron available to the body. Since iron cannot be actively eliminated from the body, its absorption via ferroportin is strictly regulated by hepcidin.
7) Conversion of Fe(II) into Fe(III)
Basolateral conversion into trivalent iron occurs via the ferroxidase hephaestin.
8) TransTransport via transferrin
Iron is circulated via transferrin. Each transferrin can bind two iron atoms. Unbound transferrin is known as apotransferrin.
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3. Iron Metabolism - Absorption
RegulATION OF
IRON aBSORPTION
DMT-1
Dcytb
Transferrin
Hephaestin
Ferroportin
HCP-1
Ferritin
Fe(III)
Fe(II)
Haem iron
Hepcidin
Absorption in the duodenum is the main regulator of iron homeostasis.
In general, only a small amount of iron is absorbed from food. An increased iron requirement leads to increased absorption, which, however, is limited and rarely exceeds 3-5 mg per day. Factors such as gastric acid secretion, pH value, intestinal motility and gastrointestinal diseases or resections also impact the absorption of dietary iron. In the event of an iron deficiency, transporters are expressed to a greater degree and in the event of adequate iron supply (or inflammation), ferroportin is inhibited by hepcidin, causing iron in the enterocytes to be eliminated in the faeces as part of the regeneration of intestinal mucosa. 1)
Hepcidin is the main negative regulator hormone in iron homeostasis. It limits the absorption of iron, preventing iron overload. 2)
Hepcidin binds to ferroportin, which is then internalised and metabolised. 3)
Iron is blocked in the enterocytes and cannot enter the bloodstream. 4)
During the physiological renewal of enterocytes (Ø life expectancy: 1-2 days), the iron contained in the cell is also eliminated. 1 2 3 4
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4. Iron Metabolism - Transport
ENTEROCYE
CONSUMER CELL
TRANSPORT
DMT-1
Transferrin
Hephaestin
Ferroportin
Transferrin receptor
Fe(III)
Fe(II)
Apotransferrin 1 2 3
Iron is transported to tissue via the bloodstream.
Transferrin is the main transport protein; it transports iron back and forth between the functional and storage compartments. As a result of its high but variable affinity for Fe(III), it ensures that no free iron is in circulation. The transferrin receptor transports iron from the bloodstream into the cells. 1)
Fe(II) enters the bloodstream via ferroportin, where it is oxidised into Fe(III) by hephaestin. 2)
Fe(III) binds to transferrin for transport. As free iron is highly reactive, in the circulation it is always bound to transferrin under physiological conditions. 3)
Iron is transported from the bloodstream into the cells via the transferrin receptor. Almost all cells express transferrin receptors that have a high affinity for iron-bound transferrin.
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5. Iron Metabolism - Usage
CONSUMER CELL
Apotransferrin
Transferrin receptor
DMT-1
Transferrin
Fe(II)
Mitochondrium
Ferritin H+ 1 2 3 4 5
Iron absorption is regulated through transferrin receptor expression.
The iron-transferrin/transferrin receptor complex is internalised through endocytosis and the iron is dissociated from the transferrin in the acidic, reductive environment of the endosome. The resulting apotransferrin is then once again released into the bloodstream. 1)
Iron-bound transferrin binds to the transferrin receptor. 2)
The iron-transferrin/transferrin receptor complex is internalised via endocytosis. 3)
The pH in the vesicle is lowered to 5-6 by the influx of H+. 4)
In a now acidic environment, iron dissociates from transferrin and is transported into the plasma of the consumer cell by DMT1. On an intracellular level, iron is used in non-erythroid cells, in particular in mitochondria metabolism. 5)
The transferrin receptor returns to the outer surface of the cell and apotransferrin is recirculated.
CONSUMER CELL
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6. Iron Metabolism - Usage
ERYTHROPOIESIS 1 2 3
BFU-ERYTHROID
Apotransferrin
EPO
EPO-Receptor
Transferrin
Fe(II)
Transferrin receptor
Haem iron
STEM CELL
CFU-ERYTHROID
Duration of erythropoiesis approx. 23 days
EPO dependence
10-13 days
Iron dependence 3-4 days
Erythrocytes account for around 44% of the total blood volume.
Every litre of blood contains 4-6e12 erythrocytes. Erythrocytes mainly consist of haemoglobin, an iron-rich, globular protein that is composed of four polypeptide chains. Each of the four chains contains one haem group with one iron ion, which can bind one oxygen molecule. Approx. 80% of the iron found in the blood is used to synthesise haemoglobin in bone marrow. 1)
The diversification of pluripotent stem cells to erythroid precursor cells is stimulated by erythropoietin, among other things. 2)
Haemoglobin is synthesised at erythroblast level. The considerable need for iron is evident in a high expression of transferrin receptors at this stage. 3)
The erythroblast matures into a reticulocyte and, ultimately, an erythrocyte over various stages.
PRO-ERYTHROBLAST
ERYTHROCYTE
RETIKULOCYTE
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ERYTHROBLAST

7. Iron Metabolism - Usage
RESPIRATORY CHain
Complex III
Cytochrome-c-Reductase
Complex I
NADH-Dehydrogenase
Complex II
Succinate-Dehydrogenase
Complex IV
Cytochrome-c-Oxidase
Complex V
ATP-Synthase
Enzymes with Heme iron
Enzymes with Iron-Sulfur Clusters
Interstitial space
Mitochodrial Matrix e- H+
Respiratory chain
Iron is an essential cofactor in complexes I-IV of the respiratory chain. It plays a key role in electron transport, in the form of iron-sulphur clusters or in haem centres.
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8. Iron Metabolism - Usage
Oxidative stress
Lysosome O2
Fe(II)
Ferritin
H2O2
Mitochondrium
Haemosiderin
H2O
Fenton’s reaction: Fe(II) + H2O2
HO•
Fe(III) + HO–+ HO•
Fe(III) 1 2 3 4 5 6
Reactive oxygen radicals are created as part of physiological metabolic processes, in particular energy generation within the mitochondria.
The resulting cell damage is usually compensated by internal cell repair mechanisms. However, in the case of excess iron, this promotes the formation of reactive oxygen radicals. In the case of persistent iron overload, this can lead to organ damage. This mainly affects the liver, which is where most iron is stored. 1)
Oxidative stress due to superoxide, a partially reduced oxygen species (PROS), occurs in the body under normal physiological conditions. This oxygen radical can have a destructive effect on biological tissue and is therefore purposely produced by the enzyme NADPH oxidase as part of the immune system’s defence against pathogens. However, it is also formed as a byproduct in the mitochondrial respiratory chain, where it is rendered innocuous by the enzyme superoxide dismutase and converted to oxygen and hydrogen peroxide. Hydrogen peroxide is in itself stable but can react with iron or copper and form radicals. 2)
Hydrogen peroxide itself is reduced to oxygen and water by catalase. The body’s defence against oxygen radicals – catalase and superoxide dismutase – is very efficient and prevents cells from being excessively damaged. 3)
In the case of an iron overload, lysosomal degradation of ferritin and haemosiderin with reduction of Fe(III) can lead to a very high concentration of Fe(II). 4)
Hydrogen peroxide can pass through biological membranes unhindered. 5)
As a result of the high concentration of Fe(II) in the reductive milieu of the lysosome, hydrogen peroxide is converted to hydroxyl radicals via Fenton’s reaction. 6)
Hydroxyl radicals are extremely reactive and there is no defence mechanism to render them harmless. In the case of a high steady-state concentration of hydroxyl radicals, lysosomes may rupture resulting in cell damage that can lead to necrosis.
IRON-OVERLOADED CELL
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9. LOSS Iron Metabolism - Loss SKIN- / MUCOSA- CELL Transferrin 2 1
Apotransferrin
There is no active elimination mechanism for iron.
1-2 mg of iron are lost every day due to the desquamation of skin and mucosal cells. Any loss of blood unfortunately also means a loss of iron. In order to ensure iron homeostasis, the daily loss must be compensated by dietary iron. Premenopausal women have a higher iron requirement because of menstruation. 1)
1-2 mg of iron is lost every day due to the desquamation of skin and mucosal cells. 2)
A key cause of increased iron loss is bleeding, whether it be due to physiological (menstruation, childbirth) or pathological reasons (trauma, gastrointestinal bleeding, e.g. because of carcinoma, etc.). 1 2
ERYTHROCYTE
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10. Iron Metabolism - Recycling
Caeruloplasmin
Transferrin
Ferroportin
Haemosiderin
Ferritin
Fe(III)
Fe(II)
LIP 1 2 3 4
MACROPHAGE IN THE SPLEEN
Most recycled iron accumulates during the renewal of erythrocytes.
The life cycle of an erythrocyte is around 120 days and approx. 200 billion need to be renewed every day, corresponding to approx. 25 mg of iron. The recycling mainly takes place in the spleen and, to a lesser extent, in the liver and bone marrow. 1)
At the end of their life cycle, erythrocytes are phagocytised by the macrophages in the reticuloendothelial system (RES) of the spleen, bone marrow and sometimes the liver. 2)
During erythrocyte metabolism, iron is once again released and is found in the labile iron pool (LIP). 3)
In the macrophages, iron is either temporarily stored in ferritin... 4)
…or recirculated for further use via ferroportin.
SPLEEN
ERYTHROCYTE
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11. Iron Metabolism - Storage
Caeruloplasmin
Transferrin
Ferroportin
Haemosiderin
Ferritin
Fe(III)
Fe(II)
LIP
Transferrin receptor
Apotransferrin 1 2 3
KUPFFER CELL
OF THE LIVER
The liver plays a central role in the iron metabolism and is the most important place for storing iron (approx. 1,000 mg).
Iron is stored in ferritin in the parenchyma cells of the liver (hepatocytes) as well as in reticuloendethelial macrophages. Kupffer cells are the resident macrophages of the liver. Their main function is phagocytosis and breakdown of ageing erythrocytes and iron recycling. Iron can be stored in the interim as ferritin in these cells or directly released into the circulation for use. The store serves as a buffer against iron deficiency and iron overload. In the event of iron overload or haemorrhage, iron is increasingly stored in haemosiderin. 1)
In iron homeostasis, excess iron is stored in ferritin. 2)
In the event of iron overload or haemorrhage in particular, more iron is stored in haemosiderin. 3)
Iron is mainly stored in the liver, but also in the spleen and bone marrow.
ERYTHROCYTE
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12. Iron Metabolism - Regulation
AT IRON DEFICIENCY
Caeruloplasmin
Transferrin
Ferroportin
Ferritin
Fe(II)
LIP
Transferrin receptor
IRP
HEPATOCYTE 1
As there is no active elimination mechanism, iron absorption must be carefully regulated.
Systemic regulation of iron metabolism controls absorption of dietary iron in the intestine and the mobilisation of iron from iron stores. Production of iron-promoting proteins (including transferrin receptors) is increased or decreased at transcription level depending on the availability of too much or too little iron. This occurs through specific mRNA sequences, known as iron-responsive elements (IRE).
Regulation at iron deficiency
In the event of an iron deficiency, the IRPs bind to the IRE-mRNA, which are found in the non-translated region of the mRNA of ferritin, DMT1, TfR1, transferrin and aminolevulinic acid synthetase, the key enzyme in haem biosynthesis. As a result, these proteins are upregulated and iron absorption increased. 1)
In the case of low intracellular iron concentration, the IRPs bind to the IRE-mRNA of ferritin, DMT1, TfR and transferrin, stimulating their production.
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13. Iron Metabolism - Regulation
Caeruloplasmin
Transferrin
Ferroportin
Ferritin
Fe(II)
LIP
Transferrin receptor
IRP
Hepcidin
REGULation
AT HIGH IRON CONCENTRATION 1 2 3 4
HEPATOCYTE
As there is no active elimination mechanism, iron absorption must be carefully regulated.
Systemic regulation of iron metabolism controls absorption of dietary iron in the intestine and the mobilisation of iron from iron stores. Production of iron-promoting proteins (including transferrin receptors) is increased or decreased at transcription level depending on the availability of too much or too little iron. This occurs through specific mRNA sequences, known as iron-responsive elements (IRE).
Regulation at high iron concentration
Iron is primarily regulated in the hepatocytes through an interaction between special cytoplasmic proteins, called iron regulatory proteins (IRP), and specific RNA structures, or iron responsive elements (IRE).
The binding affinity between IRE and IRPs is determined in particular by the intracellular iron requirement in addition to radicals and hypoxia. When there is sufficient iron supply, the binding capacity of the IRPs to the IRE-mRNA is lost, causing less DMT1 to be synthesised and, consequently, less iron to be absorbed. At the same time, the HAMP gene, which codes for hepcidin and thus triggers its production, is stimulated. 1)
In the case of sufficient iron supply, the expression of iron transport proteins is limited as the IRPs do not bind to the corresponding IRE-mRNA. 2)
Production of hepcidin is upregulated by the HAMP gene. 3)
Production of hepcidin is also promoted in the event of inflammation via IL-6. 4)
Hepcidin is secreted into the circulation and systematically impacts the release of iron from the cells.
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14. Iron Metabolism - Tables
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15. Iron Metabolism - Tables
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16. LEGAL Notice References Iron Metabolism
This content was created with expert assistance from: Dr. med. Rudolf Benz, Kantonsspital Münsterlingen, Switzerland Prof. Dr. med. Andreas Huber, Kantonsspital Aarau, Switzerland Dr. med. Franziska Demarmels-Biasiutti, Inselspital Bern, Switzerland Prof. Dr. med. Jean-Michel Gaspoz, HUG, Switzerland Dr. med. Jeroen Goede, Universitätsspital Zürich, Switzerland Prof. Dr. Willem H. Koppenol, ETH Zürich, Switzerland Prof. Dr. med. Wolfgang Korte, Kantonsspital St. Gallen, Switzerland Dr. med. Paul Pugin, Hôpital cantonal de Fribourg, Switzerland Dr. med. Kaveh Samii, HUG, Switzerland Dr. med. Jeroen Goede, University hospital of Zürich, Switzerland Prof. Dr. med. André Tichelli, Universitätsspital Basel, Switzerland Prof. Dr. med. Gérard Waeber, CHUV, Lausanne, Switzerland Prof. Dr. Dr. med. Walter A. Wuillemin, Kantonsspital Luzern, Switzerland Design: descience - A. Ulrich & N. Stadelmann, Lucerne Realisation IronAtlas: Monokel Games GmbH, Zurich Project management: Dr. Pascal Schär & Dr. Viktor Pavelic, Vifor Pharma These presentations are a port of the IronAtlas. Usage of the IronAtlas is subject to the Terms of Use. © 2015 Vifor Pharma. All rights reserved. Reproduction, publication or distribution (in full or in part) is only permitted with the prior written consent of Vifor Pharma. Exception: Images from the IronAtlas may be used for non-commercial educational purposes in unaltered form under indication of the reference ( Further information: Contact:
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17. Table of Elements Iron Metabolism IRON IONS STORED IRON Fe(III) Fe(II)
Haem iron H+
Ferritin
Haemosiderin
CHANNEL PROTEINS
TRANSPORTPROTEINE
Divalent metal transporter 1
(DMT-1)
Haem carrier protein 1
(HCP-1)
Ferroportin
Apotransferrin
Transferrin
Transferrin receptor
(TfR)
Reductases / oxidases
REGULATORY PROTEINS
Duodenal cytochrome B
(Dcytb)
Caeruloplasmin
Hephaestin
Hepcidin
iron-regulating proteins
(IRP)
Erythropoietin
(EPO)
FeS-Cluster
Catalase O2
Hydroxyl radical
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