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1.
Figure 4

Figure 4. Body iron status in mice fed four different levels of iron diets. From: Effects of Iron Deficiency and Overload on Angiogenesis and Oxidative Stress - A Potential Dual Role for Iron in Breast Cancer.

(A) Serum iron and transferrin saturation rate in mice fed 3.5 ppm iron diet (iron deficient), 35 ppm and 350 ppm iron diets (normal low and normal high iron levels), and 3500 ppm iron diet (iron overload). (B) mRNA levels of EPO by qRT-PCR in kidneys of mice fed different levels of iron diets. (C) mRNA levels of hepcidin by qRT-PCR in livers of mice fed different levels of iron diets. Significantly different among groups compared (n=3) per group.

Jinlong Jian, et al. Free Radic Biol Med. ;50(7):841-847.
2.
Figure 3

Figure 3. Proposed mechanisms of iron assimilation by Zygomycetes in conditions of elevated available serum iron. From: Iron Acquisition: A Novel Prospective on Mucormycosis Pathogenesis and Treatment.

In patients in diabetic ketoacidosis (DKA), low pH conditions cause proton-mediated displacement of ferric iron (Fe3+) from serum carrier molecules, including transferrin (T). Ferric iron is then reduced at the cell surface to ferrous iron (Fe2+). In contrast, deferoxamine (D) directly chelates iron from transferrin, resulting in ferroxamine (iron-deferoxamine complex). Ferroxamine then binds to unidentified receptor(s) on the surface of Zygomycetes. The fungus then liberates the iron from ferroxamine by reduction at the cell surface, solubilizing ferrous iron from ferroxamine. In both cases, ferrous iron is then reoxidized back to ferric iron by copper oxidase (Cu-oxidase). High affinity iron permease (rFTR1), which physically complexes with copper oxidase in yeast, transports ferric iron nearly simultaneously to the oxidation step. Note that the oxidation to ferric iron prior to transport introduces specificity to iron transport by electrochemically separating the trivalent ferric iron from other divalent cations.

Ashraf Ibrahim, et al. Curr Opin Infect Dis. ;21(6):620-625.
3.
Figure 1

Figure 1. A model for the effects of iron status on the intracellular movement and cellular release of iron in the macrophage. From: Forward Genetics Identifies Mon1a as a Critical New Protein Controlling Macrophage Iron Metabolism and Iron Recycling from Erythrocytes.

A) Low iron status increases macrophage iron export by modulating Mon1a association with vesicles. (1) Low iron increases association of Mon1a with membrane-bound vesicles containing ferroportin, (2) Increased Mon1a association leads to more ferroportin present on the membrane, (3) Iron from red blood cells (RBC) entering the macrophase is released into the cytosol and exported through ferroportin rather than stored within ferritin. B) High iron status decreases macrophage iron export by reducing Mon1a association with vesicles. (1) High iron induces hepatic production of hepcidin, a peptide hormone which is released into the serum where it binds to, and internalizes, ferroportin, 2) Reduced need for iron export decreases Mon1a association with membrane-bound vesicles containing ferroportin, thereby reducing ferroportin movement to the plasma membrane, 3) As iron export decreases iron storage in ferritin is increased.

Rebecca A. McCreedy, et al. Nutr Rev. ;67(10):607-610.
4.
Figure 3

Figure 3. Electrical consequences of iron deposition in ex-vivo myocardium.. From: Iron Deposition following Chronic Myocardial Infarction as a Substrate for Cardiac Electrical Anomalies: Initial Findings in a Canine Model.

(A) Mean measured from Remote, IRON−, and IRON+ infarct sections showed significantly greater (*, p<0.001) in IRON+ compared to Remote and IRON− sections; (B) however, mean measured from Remote, IRON−, and IRON+ infarct sections did not show any statistical difference in between the different sections.

Ivan Cokic, et al. PLoS One. 2013;8(9):e73193.
5.
Fig. 2

Fig. 2. Simplified schema describing iron metabolism. From: Regulation of Iron Absorption in Hemoglobinopathies.

Iron is absorbed by duodenal enterocytes by DMT1 or HCP1 while FPN releases it to the plasma to bind apo-TF (A). Iron circulates as holo-TF (B). Most of the iron in the body is incorporated into erythroid precursors in the bone marrow, where Hb is synthesized (C). Iron is also stored in parenchymal cells of the liver (D) and reticuloendothelial macrophages (E). Parenchymal cells, mobilizing FT-bound iron, and macrophages cells, by degrading Hb from senescent erythrocytes, release iron to the plasma onto TF for delivery to other cells (F). When iron concentration increases, HAMP is secreted by parenchymal cells, targets FPN blocking iron absorption by duodenal enterocytes and iron egress from macrophages.

Gideon Rechavi, et al. Curr Mol Med. 2008 November;8(7):646-662.
6.
Figure 7

Figure 7. Intestinal HIF-2 activates iron uptake into the small intestine. From: Intestinal Hypoxia Inducible Transcription Factors are Essential for Iron Absorption Following Iron Deficiency.

(A) Under iron-replete conditions basal iron absorption and export maintain iron homeostasis. Iron export is inhibited through high basal expression of hepcidin and hepcidin-mediated internalization and degradation of FPN. Iron uptake is limited due to decreased expression of absorptive genes. (B) Under iron-deficient conditions, decreased hepcidin expression stabilizes FPN expression resulting in increased iron export. HIF-2α activates iron absorptive genes leading to increased iron uptake into the intestine.

Yatrik M. Shah, et al. Cell Metab. ;9(2):152-164.
7.
Figure 2

Figure 2. Iron (II) accumulates in R6/2 HD striatal neurons.. From: Iron Accumulates in Huntington's Disease Neurons: Protection by Deferoxamine .

Iron (II) and iron (III) were determined by a modification of the perfusion Turnbull’s and Perl’s iron stains (see methods). A. Electron photomicrographs show striatal neurons with foci of iron (II) or (III) staining in membrane-bound structures consistent with secondary lysosomes. Quantification of iron (II) (B) and iron (III) (C) staining reveals significantly elevated iron (II) while iron (III) is unaltered. P-value: **< 0.01, n=2 and 5 neurons / mouse .

Jianfang Chen, et al. PLoS One. 2013; 2013;8(10):e77023.
8.
Figure 1

Figure 1. Systemic iron regulation. From: Iron homeostasis in the liver.

Dietary iron is absorbed through the small intestine and mainly utilized for RBC production. Hepatic and splenic macrophages recycle iron from senescent RBCs. The iron derived from recycling is used for production of RBCs. During times of iron excess the liver can store iron and during increased systemic needs the liver can mobilize iron stores for utilization.

Erik R Anderson, et al. Compr Physiol. 2013 January;3(1):315-330.
9.
Figure 4

Figure 4. Serum and liver iron after acute vs chronic dietary iron loading. From: Evidence for distinct pathways of hepcidin regulation by acute and chronic iron loading.

Serum iron concentrations after chronic iron challenge were similar or lower than those reached after acute iron challenge, in both WT and mutant mice. Liver non-heme iron content in mutants increased after chronic iron loading when compared to acute challenge (p values for the difference of medians shown above the line connecting the acute and chronic loading values). The order of hepatic iron loading was Hjv = Bmp6 > Tfr2 > Hfe. The p values for the comparison of mutant and WT iron loading are shown near or between the corresponding points on the graph.

Emilio Ramos, et al. Hepatology. ;53(4):1333-1341.
10.
Figure 2

Figure 2. Iron treatment alters iron levels of CCL-125 cells. From: Iron Loaded Ferritin Secretion and Inhibition by CI-976 in Aedes aegypti larval cells.

CCL-125 cells were treated with 0, 100–500 μM FAC, 200 or 500 μM FAC/DES (F/D), and 200 or 500 μM DES (D) for 18 h. (A) Iron is taken up by cells exposed to iron as measured by calcein fluorescent quench. *Significantly different relative to 0 (p<0.0001). aSignificantly different relative to 200 μM FAC (p<0.0001). bSignificantly different relative to 500 μM FAC (p<0.0001). (B) Cytoplasmic iron levels increase in response to iron exposure as determined by iron ICP-MS. *Significantly different relative to 0 (p<0.04). Significantly different relative to 100 μM FAC (p=0.054). aSignificantly different relative to 200 μM FAC (p<0.005). (C) Iron treatment alters membrane iron levels as determined by iron ICP-MS. *Significantly different relative to 0 (p<0.02). Significantly different relative to 100 μM FAC (p<0.0002). ΦSignificantly different relative to 200 μM FAC (p<0.0009). aSignificantly different relative to 200 μM FAC (p<0.0001). bSignificantly different relative to 500 μM FAC (p<0.0002). Data represent means ± SEM of triplicates.

Dawn L. Geiser, et al. Comp Biochem Physiol B Biochem Mol Biol. ;152(4):352-363.
11.
Figure 2

Figure 2. Key steps in mammalian cellular iron metabolism. From: Iron and cancer: more ore to be mined.

Iron circulates throughout the body bound to transferrin (TF), which can bind two atoms of ferric iron (Fe3+). TF-bound iron binds to transferrin receptor 1 (TFR1) on the plasma membrane of most cells, and the TF– [Fe3+]2–TFR1 complex is endocytosed. In the acidic environment of the endosome, ferric iron is released from TF and is reduced to ferrous iron (Fe2+) through the ferrireductase activity of STEAP3. The apotransferrin–TFR1 complex then recycles back to the cell surface, where apotransferrin participates in further rounds of iron uptake. In the meantime, ferrous iron is transported out of the endosome into the cytosol by divalent metal transporter 1 (DMT1), and enters the metabolically active pool of iron (the labile iron pool). Iron then traffics to multiple destinations. It is inserted into cytosolic enzymes that are required for DNA synthesis, such as ribonucleotide reductase, and is also used in haem synthesis and the biogenesis of iron–sulphur clusters, processes that occur partly in the mitochondria and partly in the cytosol. Excess iron is stored in ferritin, an iron storage protein. Iron leaves the cell through the activity of ferroportin, an iron efflux pump, and an oxidase such as ceruloplasmin or hephaestin, which can re-oxidize iron to ferric iron to enable the loading onto TF.

Suzy V. Torti, et al. Nat Rev Cancer. ;13(5):342-355.
12.
Figure 1

Figure 1. Iron Kinetics. Heme is absorbed by Heme carrier protein-1 (HCP-1) and released from iron by hemoxygenase-1 (HO-1), but heme uptake overall still remains controversial. From: Iron Overload Cardiomyopathy, Better Understanding of An Increasing Disorder.

Non heme iron is reduced by duodenal cytochrome b at the apical membrane of intestinal enterocytes (134), which is taken up by intestinal epithelium by the divalent metal transporter 1 (DMT1) (135,136). Ferrous iron is then transported to the basolateral portion of the cell by iron carriers and later transported into the circulation by the duodenal iron exporter Ferroportin (regulated by hepcidin) when there is a need for iron. Ferrous iron is oxidized by ceruloplasmin in non-intestinal cells and also by a homologue of ceruloplasmin, Hephaestin, in intestinal cells to ferric iron and loaded on to transferrin. With the increase in intracellular concentrations of iron, ferritin synthesis also increases. Once the storage capacity is exceeded, metabolically active iron is released intracellularly in the form of hemosiderin and toxic nontransferrin-bound forms of iron (NTBI).

Pradeep Gujja, et al. J Am Coll Cardiol. ;56(13):1001-1012.
13.
Figure 1

Figure 1. Iron Homeostasis and Hepcidin Regulation. From: Iron metabolism and the innate immune response to infection.

Dietary iron is taken up across intestinal enterocyte by a transport network that involves the apical importer DMT1 (Divalent Metal Transporter 1) and the basolateral exporter Fpn (Ferroportin). Iron circulates bound to Transferrin (Tf) and is delivered to cells by endocytosis of Tf receptors. Excess iron delivered to the liver is stored in ferritin (non-heme iron) while the majority of iron is utilization to manufacture hemoglobin (heme iron). As sensescent red cells are destroyed by macrophages in spleen and reticuloendothelial system, iron is recycle via Fpn. Entry of iron into circulation is controlled by hepcidin which is a regulatory hormone secreted by the liver, and also as part of the innate immune response. Hepcidin binds to Fpn, causing its internalization and ultimate degradation. Part of liver iron homeostasis detecting changes in iron status involves pathways sensing the saturation of circulating Tf and state of iron overload.

Erin E. Johnson, et al. Microbes Infect. ;14(3):207-216.
14.
Figure 1

Figure 1. Human iron homeostasis. From: Iron in Infection and Immunity.

A) Prior to transport into duodenal enterocytes, dietary ferric iron is reduced by ferric reductases present in the apical brush border. Ferrous iron is transported into the cell by DMT1, after which it can be used for cellular processes, stored in ferritin, or exit the cell via ferroportin (FPN). Extracellular iron is bound with high affinity by transferrin (TF). B) Erythroid precursors acquire iron via transferrin receptor (TFR) – mediated endocytosis of holo-TF, and iron is then transported into the cytoplasm by DMT1. Cytoplasmic iron can subsequently be shuttled to mitochondria for use in heme biosynthesis. C) Macrophages acquire iron via TFR-mediated endocytosis of holo-TF or recycling of senescent erythrocytes. Heme oxygenases catalyze the degradation of heme to iron, CO, and biliverdin, after which iron is transported to the cytoplasm by DMT1. Cytoplasmic iron can be used for cellular processes, stored in ferritin, or transported out of the macrophage by FPN. D) Hemoglobin or heme released upon erythrocyte lysis is avidly scavenged by haptoglobin (HPT) or hemopexin (HPX), respectively.

James E. Cassat, et al. Cell Host Microbe. ;13(5):509-519.
15.
Figure 1.

Figure 1. From: Fetal iron levels are regulated by maternal and fetal Hfe genotype and dietary iron.

(A) Serum iron levels in non-pregnant and pregnant WT and KO dams ingesting 12.5ppm and 50ppm dietary iron. Mean±SEM presented: *P<0.05 for WT non-pregnant vs. pregnant at 12.5 and 50ppm dietary iron (n≥4); §P<0.05 for KO non-pregnant vs. pregnant at 12.5 and 50 ppm dietary iron (n≥4). (B) Duodenal transporter mRNA levels in non-pregnant and pregnant WT and KO dams ingesting 50ppm dietary iron. Mean ± SEM presented: *P<0.05; WT non-pregnant vs. pregnant for Dcytb, Dmt1 and Fpn (n≥4); §P<0.05; KO non-pregnant vs. pregnant for Dcytb, Dmt1 and Fpn (n ≥ 4). (C). Non-heme liver iron levels in non-pregnant and pregnant WT and KO dams ingesting 12.5ppm and 50ppm dietary iron. Mean ± SEM presented: *P<0.001 for WT non-pregnant vs. pregnant at 50ppm dietary iron (n ≥ 4); §P<0.001 for KO non-pregnant vs. pregnant at 12.5 ppm and 50 ppm dietary iron (n≥4). (D). Hepatic transporter mRNA levels in non-pregnant and pregnant WT and KO dams ingesting 50ppm dietary iron. Mean ± SEM presented: *P<0.05; WT non-pregnant vs. pregnant for Tfr1 and Cp (n ≥ 4); §P<0.05; KO non-pregnant vs. pregnant for Tfr1, Fpn and Cp (n ≥ 4)

Sara Balesaria, et al. Haematologica. 2012 May;97(5):661-669.
16.
Figure 2

Figure 2. From: Performance and sex difference in ultra-triathlon performance from Ironman to Double Deca Iron ultra-triathlon between 1978 and 2013.

Cycling split times for the annual three fastest women and men from Ironman to Double Deca Iron ultra-triathlon for Ironman women (Panel A), Double Iron women (Panel B), Triple Iron women (Panel C), Quintuple Iron women (Panel D), Ironman men (Panel E), Double Iron men (Panel F), Triple Iron men (Panel G), Quadruple Iron men (Panel H), Quintuple Iron men (Panel I), Deca Iron men (Panel J), Double Deca Iron men (Panel K).

Christoph A Rüst, et al. Springerplus. 2014;3:219.
17.
Figure 3

Figure 3. From: Performance and sex difference in ultra-triathlon performance from Ironman to Double Deca Iron ultra-triathlon between 1978 and 2013.

Running split times for the annual three fastest women and men from Ironman to Double Deca Iron ultra-triathlon for Ironman women (Panel A), Double Iron women (Panel B), Triple Iron women (Panel C), Quintuple Iron women (Panel D), Ironman men (Panel E), Double Iron men (Panel F), Triple Iron men (Panel G), Quadruple Iron men (Panel H), Quintuple Iron men (Panel I), Deca Iron men (Panel J), Double Deca Iron men (Panel K).

Christoph A Rüst, et al. Springerplus. 2014;3:219.
18.
Figure 1

Figure 1. From: Performance and sex difference in ultra-triathlon performance from Ironman to Double Deca Iron ultra-triathlon between 1978 and 2013.

Swimming split times for the annual three fastest women and men from Ironman to Double Deca Iron ultra-triathlon for Ironman women (Panel A), Double Iron women (Panel B), Triple Iron women (Panel C), Quintuple Iron women (Panel D), Ironman men (Panel E), Double Iron men (Panel F), Triple Iron men (Panel G), Quadruple Iron men (Panel H), Quintuple Iron men (Panel I), Deca Iron men (Panel J), Double Deca Iron men (Panel K).

Christoph A Rüst, et al. Springerplus. 2014;3:219.
19.
Figure 4

Figure 4. From: Performance and sex difference in ultra-triathlon performance from Ironman to Double Deca Iron ultra-triathlon between 1978 and 2013.

Overall race times for the annual three fastest women and men from Ironman to Double Deca Iron ultra-triathlon for Ironman women (Panel A), Double Iron women (Panel B), Triple Iron women (Panel C), Quintuple Iron women (Panel D), Ironman men (Panel E), Double Iron men (Panel F), Triple Iron men (Panel G), Quadruple Iron men (Panel H), Quintuple Iron men (Panel I), Deca Iron men (Panel J), Double Deca Iron men (Panel K).

Christoph A Rüst, et al. Springerplus. 2014;3:219.
20.
Figure 1

Figure 1. Key features of systemic iron homeostasis in humans. From: Iron and cancer: more ore to be mined.

Dietary iron (predominantly in the form of ferric iron (Fe3+)) is absorbed in the duodenum through the concerted action of a reductase, such as duodenal cytochrome b (DCYTB), which produces ferrous iron (Fe2+), and divalent metal transporter 1 (DMT1). Iron exits the basolateral surface of the enterocyte through the iron efflux pump ferroportin, which functions together with the oxidase hephaestin to oxidize ferrous iron to form ferric iron, which is loaded onto transferrin (TF). The diferric iron transferrin complex (TF–[Fe3+]2) circulates through the bloodstream to deliver iron to sites of utilization. Principal among these sites is the bone marrow, where iron is used in the synthesis of haemoglobin and red blood cells (RBCs). RBCs circulate for approximately 90 days before they are catabolized by macrophages of the reticuloendothelial (RE) system. Iron is released from catabolized haem and effluxed out of the macrophage through the action of ferroportin, where it is loaded onto TF in the bloodstream, in a process termed iron recycling. TF–[Fe3+]2 is also delivered to peripheral tissues and the liver, which is the primary organ for the storage of excess iron. Although small amounts of iron are lost through desquamation, there is no excretory pathway for iron, so levels of iron in the body are primarily regulated at the absorption step. Excess iron induces the synthesis of the peptide hormone hepcidin (HP), which serves as a master regulator of systemic iron homeostasis. HP binds to ferroportin and triggers its degradation, inhibiting both delivery of dietary iron through the enterocyte and iron recycling through the macrophage. HP is also induced in response to inflammatory cytokines and thus contributes to the anaemia of cancer.

Suzy V. Torti, et al. Nat Rev Cancer. ;13(5):342-355.

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