Educational guide
Iron Metabolism - an overview | ScienceDirect Topics
Chapters and Articles You might find these chapters and articles relevant to this topic. Overview of iron metabolism Iron is an essential element required by humans for their survival and development. From 13 mg to 18 mg of heme or nonheme daily dietary iron,
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Chapters and Articles
You might find these chapters and articles relevant to this topic.
Overview of iron metabolism
Iron is an essential element required by humans for their survival and development. From 13 mg to 18 mg of heme or nonheme daily dietary iron, only 1–2 mg is absorbed through the duodenum into the circulation and is distributed to different parts of the body, to be used for various metabolic purposes.1 The three main cell-types involved in iron metabolism are the iron-absorbing duodenal enterocytes, the iron-recycling reticuloendothelial macrophages, and the iron-storing liver hepatocytes. As shown in Figure 28.1, uptake of nonheme iron (mostly ferric iron) begins when a ferric reductase duodenal cytochrome b (Dcytb), located on the apical surface of enterocytes, reduces the poorly bioavailable ferric iron (Fe3+) to ferrous iron (Fe2+). The low pH of proximal duodenum, along with an acidic climate of the brush border membrane, maintains iron in the Fe2+ state. The presence of acidic substances in the lumen, such as vitamin C, enhances nonheme iron absorption as it supplies H+ ions and reduces Fe3+ to Fe2+, making it more soluble and thus bioavailable. Conversely, tannins present in tea and fruit juices, phytates present in cereals and polyphenolic compounds found in all plant products, inhibit the absorption of dietary nonheme iron.2
Figure 28.1. Cell types involved in iron absorption and circulation.
The mechanism of iron absorption and circulation, along with the roles of participating proteins, are briefly shown. (a) Mature villus duodenal enterocytes absorb heme and nonheme iron. (b) Hepatocytes store iron as well as produce hepcidin. Here, both TBI and NTBI uptake of iron occurs. (c) Macrophages engulf senescent erythrocytes, particularly in the spleen, and recycle iron back into circulation through ferroportin. Processes in (b) and (c) are common to both heme and nonheme iron transport and utilization.
Figure adapted from Ref. [5].The Fe2+ iron in the lumen can be transported across the brush border membrane into the enterocyte via the protein divalent metal transporter-1 (DMT1). Heme iron uptake also occurs at the surface of enterocytes via heme carrier protein, and is succeeded by the action of intracellular heme oxygenase that degrades heme to produce the Fe2+ iron. Regardless of the type of iron consumed, once inside the enterocytes, iron enters the proposed labile iron pool (LIP) that may act as an iron reservoir for various cellular activities, while excess iron is stored in the protein ferritin that can hold up to 4500 iron atoms. After 2–3 days, when enterocytes slough from the gut into the lumen, the unabsorbed iron present in these cells is lost via feces.1,2
Iron is translocated outside the enterocytes and brought into the circulation through the sole known mammalian transmembrane iron-exporter, ferroportin (encoded by the gene SLC40-A1). This is a unidirectional ferrous exporter, and is expressed on all cell types involved in iron transport, including the basolateral surface of the enterocytes, which is in constant access with the circulation.3 During the exit of iron from the enterocyte, ferroportin is assisted by the ferroxidase hephaestin (encoded by the gene HEPH), which converts Fe2+ to Fe3+, whereas the ferroxidase ceruloplasmin (encoded by the gene CP) assists in the loading of Fe3+ onto transferrin. Transferrin, the iron carrier protein in circulation, transports iron throughout the body and binds to the transferrin receptor-1 (TFR1) (encoded by the gene TFRC), present on the surface of all cells involved in iron transport. The complex of diferric transferrin-TFR1 is internalized into a vesicle, and taken up within the cell. The low pH of vesicle and intracellular DMT1 on the vesicle surface assist in the release of iron from this complex into the cell cytoplasm.4 Once the iron is released into the cytoplasm, the complex without iron is then recycled back to the cell surface for further iron uptake. Each TFR1 can undertake approximately 100 such recycling processes in its lifetime, and thereby function to bring iron into the cells. One of the ways, in which the cells maintain intracellular iron levels is by changing the expression of TFR1 on the cell surface, depending on cellular iron-requirement.4,5 Unlike TFR1, transferrin receptor-2 (TFR2) is expressed mainly on hepatocytes. It has been proposed that TFR2 binds to HFE, the hemochromatosis protein, and may act as a sensor of diferric transferrin in the circulation.6,7
Following absorption, the majority of the iron is utilized in the process of erythropoiesis. Approximately 2 million red blood cells (RBCs) are synthesized every second in the bone marrow, which requires 25–30 mg of iron per day for heme synthesis. Where the total amount of iron in the body is 3.0–4.0 g, about 2.5 g is bound to hemoglobin. In addition, iron is utilized by various cell types in several pathways, for example, in the synthesis of myoglobin, an oxygen binding protein found in the muscle tissues of vertebrates, aconitase, which converts citrate to isocitrate in the citric acid cycle, and the membrane bound cytochromes, which conduct redox reactions in electron transport chain in the mitochondria. Furthermore, iron acts as a cofactor for ribonucleotide reductase, which converts ribonucleotides to deoxyribonucleotides, which are eventually used in DNA synthesis.1,2,5
Systemic and Cellular Regulation of Iron
Free iron can easily accept and donate electrons, and catalyze the Fenton reaction to generate hydroxyl radicals. These reactive oxygen species (ROS) can severely damage cells and tissues, and both iron and hydrogen peroxide, which participate in the Fenton reaction are capable of oxidizing a wide variety of biological substrates.8 Under physiological conditions, ROS, such as superoxide anions and hydroxyl radicals, are generated during normal mitochondrial respiration. These contribute to the pathology of cellular damage, and also in the redox signaling to other cell organelles.9 The resultant oxidative stress is usually combated by cellular antioxidant enzymes like superoxide dismutases and glutathione peroxidases, which catalyze the conversions of superoxide radicals into oxygen and hydrogen peroxide, and the conversion of free hydrogen peroxide to water, respectively.10 The iron-sequestering proteins such as transferrin, ceruloplasmin and ferritin also provide protection against oxidative stress. These bind to free iron and thereby limit its availability to catalyze the Fenton reaction, and enhance oxidative stress. However, when iron levels exceed beyond the iron-sequestering capacity of the iron-binding proteins, it ultimately renders the inherent antioxidant protection systems insufficient in handling the excess free iron, thereby causing cellular damage that is beyond repair. The damage is particularly accelerated due to the reduction in the levels of cellular antioxidants, such as superoxide dismutase and vitamins A, C, and E under iron overloaded conditions, which normally help to scavenge free radicals.11,12 Moreover, there is no physiological pathway for the excretion of excess iron, except by blood loss and the natural means of minimal iron loss from the body, occurring as a result of sloughing of mucosal cells and/or menstruation.1 Thus, although iron is essential for survival, maintaining iron homeostasis is crucial because excess free iron is extremely toxic.
Accordingly, iron is regulated at the systemic as well as cellular level. Systemic iron regulation is mediated by the 25-mer bioactive hepcidin (2.7 kDa), the most predominant isoform of hepcidin that circulates in the human blood,13 at a concentration of 1.1-55 ng/mL14 (Figure 28.2). It is produced from an 84-mer preprohormone, the preprohepcidin that is cleaved by signal peptidases to produce the 60-mer prohepcidin, followed by the action of furin-like convertases that cleave prohepcidin to yield the 25-mer bioactive hepcidin.
Figure 28.2. Significant sites of cleavage in preprohepcidin (84-mer).
Sites of action of signal peptidase and furin convertase are shown in the figure. Cleavages eventually lead to the bioactive hepcidin-25.
Typically, hepcidin expression is suppressed by hypoxia and IDA and elevated by lipopolysaccharide (LPS), inflammatory stimuli such as interleukin (IL)1 and IL6, and high iron levels.15,16 Increased systemic iron levels lead to an increase in hepcidin levels in the circulation and in the urine, where it offers antibacterial protection.16,17 Circulatory hepcidin binds to ferroportin, its receptor protein on cell-surfaces, to form a hepcidin–ferroportin complex, which is internalized via endocytosis, followed by proteolytic degradation of both hepcidin and ferroportin in the lysosomes.18 Since ferroportin functions as an iron exporter, its degradation inhibits iron release from enterocytes, macrophages, and placental cells into the circulation, thus preventing further systemic iron elevation. In contrast, systemic iron deficiency leads to a decrease in hepcidin production,16 and a resultant increase in iron efflux from cells, which eventually raise systemic iron levels. Thus, hepcidin plays a pivotal role in regulating systemic iron levels in the body by inhibiting duodenal iron absorption, and controlling the release and recycling of iron by macrophages, and iron mobilization by hepatocytes.
Hepcidin (encoded by the gene HAMP) transcription, and subsequently systemic iron regulation, is affected by the bone morphogenetic proteins (BMP)-SMAD, Janus kinase/signal transducer and activator of transcription-3 (JAK-STAT) and hypoxia-inducible factor (HIF) pathways, as summarized in Figure 28.3. Briefly, intracellular iron stores influence the binding of BMPs (particularly BMP6) to their receptors on the cell surface, and the membrane-bound hemojuvelin (mHJV) acts as a BMP co-receptor to assist in this process. This leads to phosphorylation and activation of the intracellular SMAD proteins, which transmit a signal to the nucleus to increase HAMP transcription in the cells.19 Also, during inflammation, IL6 induces HAMP transcription via the JAK/STAT pathway19 (Figure 28.3a). When iron stores are low, mHJV is cleaved by furin and/or matripase 2 (a transmembrane protease encoded by the gene TMPRSS6, expressed predominantly in liver) to form soluble HJV (sHJV). The sHJV disrupts the BMP-mediated activation and, instead, downregulates HAMP transcription20 (Figure 28.3b). Apart from these pathways, HAMP transcription is also regulated by the kinase/mitogen activated protein kinase pathway (ERK/MAPK),21 the growth differentiation factor (GDF) 15,22 and twisted grastrulation (TWSG1).23
Figure 28.3. (a) Pathways leading to transcriptional upregulation of hepcidin. The physiological mechanisms that lead to HAMP transcription are shown. The complex of SMAD proteins enter the nucleus, bind to the promoter region of hepcidin gene and stimulate HAMP transcription. Also, the STAT3 dimer formed as a result of IL6 binding to its receptor, led to the upregulation of hepcidin. High liver iron stores promote hepcidin synthesis via the BMP pathway. (b) Pathways leading to transcriptional downregulation of hepcidin. The mechanisms that lead to HAMP downregulation are shown. Both furin and matripase 2 are able to cleave mHJV to soluble HJV. The soluble HJV does not allow a stable complex to be formed between BMP ligands and receptors, thus inhibiting HAMP transcription via the BMP pathway. Hypoxia inducible factor increases the transcription of genes that would cleave the mHJV to soluble HJV.
Adapted from Ref. [27].Cellular iron homeostasis is mediated by binding of the two iron regulatory proteins (IRP), IRP1 and IRP2, to iron responsive elements (IREs) on the mRNA of some iron-regulated genes. Binding of IRP1 to IRE in 5’ untranslated regions (UTRs) of transcripts prevents protein synthesis, whereas binding of IRP1 to IREs in the 3’ region provides stability to mRNA, and allows translation into proteins. The binding of the IRPs to the IREs is regulated by the presence of iron (Figure 28.4).
Figure 28.4. Cellular regulation of iron, by iron regulatory proteins (IRPs).
Regulation of intracellular iron levels by IRPs has been shown. Binding of IRPs to IREs in 5’ UTR and 3’ UTR lead to different effects. IRP binding to 5’ IREs result in the inhibition of protein production, whereas binding to 3’ IREs favor protein production.
When cellular iron levels are sufficient or in excess, an iron–sulfur cubane (4Fe–4S) is formed, preventing the binding of IRP1 to the IRE in 5’ UTR of ferritin and ferroportin transcripts. This permits translation into proteins that favor more iron storage within cells, and more iron efflux, respectively, and prevent cellular iron overload. In contrast, under cellular iron depletion, IRP1 is iron-free and can therefore bind to the IREs in 3’ UTR on transcripts of genes encoding TFR1 and intestinal DMT1. In doing so, it stabilizes the mRNAs, increases the expression of both proteins, and thereby facilitates increased cellular iron uptake to eliminate cellular iron deprivation. Thus, the IRP–IRE network maintains cellular iron levels, and is not limited exclusively to these exemplified transcripts.5
Iron Homeostasis and Disorders
The significance of body iron homeostasis can be realized by reflecting on the diseases and conditions, in which iron homeostasis is disturbed. Iron deficiencies can be broadly classified into absolute iron deficiency, and functional iron deficiency. The former, also referred to as IDA, is characterized by depleted iron stores and low circulating iron levels that limit the availability of iron for RBC synthesis. IDA can occur either due to excessive blood loss, or pregnancy, when there is increased demand for iron, or malnutrition, when there is decreased supply of iron. Approximately one third of the world population is believed to be suffering from IDA, which could manifest in a wide variety of pathophysiological effects, including the developmental retardation in children. Currently, the most commonly prescribed treatment to alleviate IDA is to increase body iron levels by using approximately 200 mg of ferrous salts per day. However, the unabsorbed iron salts cause nausea, abdominal pain, and constipation. To combat these symptoms, low doses of iron salts between 50 mg and 100 mg of iron have been proposed.24 On the other hand, functional iron deficiency is more complex, as seen during infection/inflammation and cancer, and is referred to as anemia of inflammation, or anemia of chronic disease. This is typically characterized by low serum–iron levels, despite replete iron stores due to iron-restricted erythropoiesis.5,24
Iron overload could be acquired or functional. Some examples of acquired iron overload are the iron overdose in children, which is the commonest poisoning in children, and iron overload as a result of repeated blood transfusions.24 Bantu siderosis is yet another form of acquired iron overload in some people of African descent that occurs due to the consumption of brewed beer made in large iron vessels.25 Functional iron overload, referred to as hereditary hemochromatosis, is the most frequent genetic disorder in Caucasians, and results from defects in single or multiple genes of iron metabolism, such as HFE, HJV, HAMP, TFR2, SLC40-A1, TF, and CP,26 encoding the proteins HFE, HJV, hepcidin, TFR2, ferroportin, transferrin, and ceruloplasmin, respectively. Under hemochromatosis, intestinal iron absorption can exceed iron loss by approximately 3 mg/day,26 attaining total body iron levels of up to 50 g, as compared to the typical 3–4 g. The effect of this can be tissue specific, for example, liver possesses high levels of antioxidants and cytoprotective enzymes, and therefore requires a substantially high level of liver iron overload for observable toxic effects of iron. Alternatively, in the reticuloendothelial cells, for example, macrophages, only about a two- to threefold increase in cellular iron would lead to changes in normal cell functions.24,28 Accordingly, where hemochromatotic patients show a 10- to 20-fold increase in liver iron stores, before clinical manifestations are observed, patients with Parkinson’s disease show only a twofold increase in iron content in substantia nigra pars compacta (i.e., a section of the brain),29 thus demonstrating the tissue specific effect of iron.
In essence, normally, the systemic and cellular iron homeostatic pathways operate in amalgamation to minimize the availability of free iron for the Fenton reaction and, thus, control excess iron-mediated tissue injury. Since alcohol intake is an additional reason, the aforementioned genetic, epigenetic, and nutritional factors that cause digression from the normal iron regulation are not the only reasons for disruption in iron homeostasis.
URL: https://www.sciencedirect.com/science/article/pii/B9780128007730000288
Chapter
Iron Metabolism
Iron is one of the essential cofactors important for the correct functioning of many bacterial metabolic enzymes. The ability of M. catarrhalis to acquire sufficient iron is therefore crucial for the organism’s optimal growth and fitness. In the human host, iron is always found ‘hidden’ as complexes with host proteins such as haemoglobin, haem, transferrin or lactoferrin, these complexes sequestering iron from the environment and helping form part of the innate immune defence against bacterial infection. These host complexes can, however, be counteracted by several multicomponent iron metabolism systems present in M. catarrhalis (Fig. 88.3).
Figure 88.3. A schematic diagram of M. catarrhalis iron metabolism. Iron acquisition is mediated by several surface-associated proteins. These include LbpA/LbpB, TbpA/TbpB, HumA, MhuA and CopB, which function as the receptors for lactoferrin, transferrin, haemoglobin, haem and ferric ions, respectively. After binding of iron–protein complexes to the receptors, iron is released from the protein complex and transported across the outer membrane into the periplasmic compartment at the expense of energy provided by the TonB–ExbB–ExbD complex. The iron is then bound by the periplasmic FbpA or AfeA and further transported across the inner membrane by an ATP-binding cassette transporter (FbpABC and AfeABCD). Free iron within the cytosol is stored either in complex with iron storage protein, the bacterioferritins (BfrA and BfrB), or used as a cofactor for various enzymatic activities. OM, outer membrane; IM, inner membrane.
M. catarrhalis iron metabolism is initiated via the acquisition of host iron complexes. This process is mediated by several M. catarrhalis surface-associated iron-binding molecules including lactoferrin-binding protein A (LbpA) and B (LbpB), transferrin-binding protein A (TbpA) and B (TbpB), haem utilization protein (HumA), haemoglobin utilization protein (MhuA) and outer-membrane protein CopB. The molecular structure and virulence characteristics of these proteins are further described in the Structure and Virulence Mechanisms section. Another unrelated mechanism is the degradation of haem catalysed by Moraxella haem oxygenase [102,115]. The expression of iron-binding proteins is regulated by the surrounding iron concentration, a process that may involve an iron-responsive repressor, a ferric uptake regulator (Fur) [116], the up-regulated expression of lbpA, lbpB, tbpB and copB genes, as well as inner-membrane iron-transport factors (TonB–ExbB–ExbD), all of which have been associated with the response to iron starvation [101,117]. Indeed, strains lacking the Fur regulation system show retarded growth, due to the uncontrolled over-expression of iron acquisition systems, leading to toxic levels of bacterial intracellular iron [116,118]. Further, overexposure of iron-binding proteins to the host immune system, as observed in a Fur-deficient strain, renders the bacteria highly susceptible to the bactericidal activity of normal human serum [116]. In fact, a recent study using high-throughput genome-wide screening technology, genomic array footprinting (GAF), identified a further five genes essential for M. catarrhalis growth during iron starvation [113]. These included genes encoding the oxygen-independent coproporphyrinogen-III oxidase-like protein (YggW), ATP-dependent RNA helicase (RhlB), ribonuclease D (Rnd) and two hypothetical proteins of unknown function (MCR_0457 and MCR_0996). YggW is predicted to catalyse the oxidative decarboxylation of coproporphyrinogen-III to protoporphyrinogen, which could indicate that YggW may be involved in haem shuffling between the periplasm and cytoplasm as well as in loading cytochromes with haem during M. catarrhalis iron metabolism [113,119]. The RhlB protein is a subunit of a degradasome complex that is involved in RNA degradation. RhlB together with Rnd are likely to confer M. catarrhalis with the ability to adapt to changing environmental conditions, such as iron depletion, via the regulation of gene expression.
Subsequent iron transportation from the bacterial periplasmic compartment to the cytosol is operated by the Fe3+ ABC transporter complex (FbpABC), chelated iron ABC transporter complex (AfeABCD) and TonB-ExbB-ExbD [102,120,121]. M. catarrhalis also expresses intracellular iron uptake and storage bacterioferritins (BfrA and BfrB), which store free iron in the ferric form, thereby preventing the cellular toxicity that would be associated with free iron, whilst also helping to confer protection against oxygen radicals [102,122].
URL: https://www.sciencedirect.com/science/article/pii/B9780123971692000883
5.1 Overview of Iron Metabolism
Iron is a precious metal for the organism because of its unsurpassed versatility as a biological catalyst. It is involved in a broad spectrum of essential biological functions such as oxygen transport, electron transfer, and DNA synthesis. Hence, iron is an essential element for growth and survival. However, the very chemical properties of iron that allow this versatility also create a paradoxical situation making acquisition by the organism of this, the fourth most abundant element in the Earth’s crust, exceedingly difficult. At pH 7.4 and physiological oxygen tension, the relatively soluble ferrous ion is readily oxidized to the ferric ion, which upon hydrolysis forms virtually insoluble ferric hydroxides. The concentration of aquated Fe(III) in aqueous solutions (pH 7.4) cannot exceed 10−17 M. Moreover, unless appropriately “shielded,” iron promotes the formation of harmful oxygen radicals, which ultimately cause peroxidative damage to vital cell structures. Because of its virtual insolubility and potential toxicity, iron must be constantly chaperoned; specialized mechanisms and molecules for the acquisition, transport, and storage of iron in a soluble, nontoxic form have evolved to meet the iron requirements of cells and organisms. Moreover, organisms are equipped with sophisticated mechanisms that prevent the accumulation of a catalytically active intracellular iron pool, while maintaining sufficient concentrations of the metal for metabolic use (Harrison and Arosio, 1996; Richardson and Ponka, 1997; Ponka et al., 1998; Aisen et al., 2001; Eaton and Qian, 2002; Hentze et al., 2004; Andrews, 2005; Hentze et al., 2010; Sheftel et al., 2012).
Iron, both in its heme and nonheme forms, is present in every cell in the body; most cells, except for mature red cells and terminally differentiated lens epithelium, have the capacity to acquire iron. However, cellular iron acquisition and its proper intracellular targeting into functional iron proteins depend on an array of other proteins. “Traditional” proteins involved in iron metabolism include transferrin, transferrin receptor, and ferritin, but a remarkable flurry of activity since the 1990s has identified a large number of novel genes whose products have emerged as important players in iron metabolism (Table 1).
TABLE 1. Some Proteins Involved in Iron Metabolism
| Protein | Function | Result of deficiency | Reference(s) |
|---|---|---|---|
| ABCB7 | Involved in Fe-S biosynthesis | XLSA with ataxia | Lill and Muhlenhoff, 2005; Napier et al., 2005 |
| ABCB10 (ABC-me) | Mitochondrial transport function related to heme synthesis; interacts with mitoferrin-1 and enhances its stability in erythroid cells | Nearly complete eradication of primitive erythropoiesis at day E 10.5; death at day 12.5 of gestation | Shirihai et al., 2000; Chen et al., 2009; Hyde et al., 2012 |
| ALA-S2/eALA-S | First enzyme of heme synthesis; erythroid-specific 5-aminolevulinic acid synthase | X-linked sideroblastic anemia | Cox et al., 1991; Fitzsimons and May, 1996; Ponka, 1997 |
| Bone morphogenic proteins 2/4/6 (BMP 2/4/6) | Positive regulator of hepcidin | Iron overload (for BMP-6) | Babitt et al., 2006, 2007; Kautz et al., 2008; Andriopoulos et al., 2009 |
| Ceruloplasmin (Cp) | Ferroxidase; involved in promoting release of Fe from cells | Neurodegeneration; iron loading of brain and liver; microcytic anemia | Hellman et al., 2002; Sheftel et al., 2012 |
| NRAMP2/DMT-1 | Membrane transporter for Fe2+ | Hypochromic microcytic anemia | Fleming et al., 1997; Gunshin et al., 1997; Mims et al., 2005; Hentze et al., 2010 |
| Cytochrome b reductase 1/duodenal cytochrome b (Dcytb) | Ferric reductase | No noticeable defect | McKie et al., 2001; Gunshin et al., 2005 |
| Ferritin (H and L) | Cellular Fe storage | H, embryonic lethality; L, unknown | Harrison and Arosio, 1996; Richardson and Ponka, 1997; Ferreira et al., 2000; Arosio et al., 2009 |
| Ferrochelatase | The last enzyme of heme synthesis; inserts Fe2+ into protoporphyrin IX | Erythropoietic protoporphyria | Cox, 1997; Ponka, 1997; Ajioka et al., 2006 |
| Ferroportin/MTP1/Ireg1 | Fe export from cells | Hemochromatosis type IV (Ferroportin disease) | Donovan et al., 2000; Pietrangelo, 2004a; Hentze et al., 2010 |
| Frataxin | Fe-binding chaperone for Fe-S cluster synthesis | Friedreich ataxia | Gerber et al., 2003; Lill and Muhlenhoff, 2005; Napier et al., 2005; Li et al., 2008; Huang et al., 2009; Sheftel and Lill, 2009; Sheftel et al., 2010 |
| Hereditary hemochromatosis protein (HLA-H/HFE) | Binds TfR; restricted expression (enterocytes, macrophages); regulates interaction of Tf with TfR1/TfR2 | Hemochromatosis type I (variable penetrance) | Feder et al., 1996; Pietrangelo, 2004; Fleming and Ponka, 2012; Sheftel et al., 2012 |
| Heme oxygenase 1 (HO-1) | Catalyzes the release of iron from protoporphyrin IX; involved in the recycling of hemoglobin Fe | Severe anemia and inflammation | Yachie et al., 1999; Maines, 2004; Maines and Gibbs, 2005; Abraham and Kappas, 2008 |
| Hemojuvelin (HJV/HFE2/RGMc) | Coreceptor for BMP-2 and 4; binds neogenin | Juvenile hemochromatosis (subtype of type II) | Papanikolaou et al., 2004; Babitt et al., 2007; Zhang et al., 2008 |
| Hepcidin | Negative regulator of iron absorption and iron release from macrophages; causes the internalization and degradation of ferroportin | Juvenile hemochromatosis (subtype of type II); overexpression of hepcidin causes severe Fe deficiency anemia | Park et al., 2001; Nicolas et al., 2002; Nemeth et al., 2004; Ganz 2005, 2011; Fleming and Ponka, 2012; Sheftel et al., 2012 |
| Hephaestin | Regulation of Fe export from enterocytes (membrane-bound Cp homolog) | Hypochromic microcytic anemia (sex-linked anemia in mice) | Vulpe et al., 1999; Sheftel et al., 2012 |
| Iron regulatory proteins (IRP 1 and 2) | Fe “sensors”; bind to IREs | IRP1, Elevated ferritin in brown fat and kidney; IRP2, microcytic anemia, erythropoietic protoporphyria, neurodegeneration | Richardson and Ponka, 1997; Mikulits et al., 1999; Pantopoulos, 2004; Cooperman et al., 2005; Meyron-Holtz et al., 2004; Hentze et al., 2010; Sheftel et al., 2012 |
| Huntingtin | Transferrin receptor trafficking | Huntingtin knockout zebrafish have microcytic anemia | Hilditch-Maguire et al., 2000; Lumsden et al., 2007 |
| Melanotransferrin | Unknown | Unknown | Richardson and Ponka, 1997; Suryo Rahmanto et al., 2012 |
| Mitochondrial ferritin | Mitochondrial Fe storage (?) | Unknown; high expression in “ring” sideroblasts | Levi et al., 2001; Napier et al., 2005; Nie et al., 2005; Richardson et al., 2010; Sheftel et al., 2012 |
| Mitoferrin-1 (erythroid specific), Mitoferrin-2 (ubiquitous) | Involved in mitochondrial iron delivery | Mitoferrin-1, Hypochromic, microcytic anemia; erythroid maturation arrest | Shaw et al., 2006 |
| Sec15l1 | “Vesicle docking” | “Hemoglobin-deficit” (hbd) mice | Lim et al., 2005; White et al., 2005; Zhang et al., 2006 |
| Sideroflexin 1 | Mitochondrial transport function related to Fe metabolism | Siderocytic anemia (mice) | Fleming et al., 2001 |
| Steap3 (six-transmembrane epithelial antigen of the prostate 3) | Endosomal ferrireductase | Hypochromic anemia (mice) | Ohgami et al., 2005 |
| Matriptase-2 (TMPRSS6) | Serine protease regulating the processing of hepcidin | Microcytic anemia | Du et al., 2008; Finberg et al., 2008 |
| Transferrin (Tf) | Fe(III)-carrier in plasma | Severe anemia (iron unavailable for erythropoiesis; iron overload | Richardson and Ponka, 1997; Ponka, 2002 |
| Tf receptor (TfR) | Membrane receptor for Fe2-Tf | Embryonic lethality | Richardson and Ponka, 1997; Levy et al., 1999; Ponka et al., 1999; Aisen, 2004; Sheftel et al., 2012 |
| TfR2 | Required for the regulation of hepcidin | Hemochromatosis type III | Kawabata et al., 1999; Camaschella et al., 2000; Chen and Enns, 2012 |
| ZIP14 | Putative mediator of non-Tf-bound iron uptake in hepatocytes | Unknown | Liuzzi et al., 2006 |
IRE, iron-responsive element; XLSA, X-linked sideroblastic anemia.
The bodies of adult men and women contain 55 mg and 45 mg of iron per kilogram body weight, respectively. Normally, 70-80% of total body iron is present in hemoglobin in circulating erythrocytes. In vertebrates, iron is transported within the body between sites of absorption, storage, and utilization by the plasma glycoprotein transferrin, which binds iron(III) very tightly but reversibly. The turnover of transferrin iron is roughly 30 mg/24 h; normally, about 80% of this iron is transported to the bone marrow for hemoglobin synthesis in developing erythroid cells. Senescent erythrocytes are phagocytosed by macrophages of the reticuloendothelial system; the heme moiety is then split from hemoglobin and catabolized enzymatically via heme oxygenase 1 (HO-1). Most of the iron that is liberated from its confinement within the tetrapyrrole ring inside macrophages is returned to the circulation. The remaining 5 mg of the daily plasma iron turnover is exchanged with nonerythroid tissues, primarily the liver. About 1 mg of dietary iron is absorbed per 24 h and the total iron balance is maintained by a daily loss of 1 mg via nonspecific mechanisms (mostly cell desquamation) (Ponka et al., 1998; Ponka, 2003; Andrews, 2005; Fleming and Ponka, 2012). This process represents an extraordinarily delicate balancing act, given that iron amounts to about 1/100,000,000th part (weight/weight) of the human body.
URL: https://www.sciencedirect.com/science/article/pii/B978044459453200041X
5 Biological Function and Metabolism
5.1 Overview of Iron Metabolism
Iron is a precious metal for the organism because of its unsurpassed versatility as a biological catalyst. It is involved in a broad spectrum of essential biological functions such as oxygen transport, electron transfer, and DNA synthesis. Hence, iron is an essential element for growth and survival. However, the very chemical properties of iron that allow this versatility also create a paradoxical situation making acquisition by the organism of this, the fourth most abundant element in the Earth’s crust, exceedingly difficult. At pH 7.4 and physiological oxygen tension, the relatively soluble ferrous ion is readily oxidized to the ferric ion, which upon hydrolysis forms virtually insoluble ferric hydroxides. The concentration of aquated Fe(III) in aqueous solutions (pH 7.4) cannot exceed 10−17 M. Moreover, unless appropriately “shielded,” iron promotes the formation of harmful oxygen radicals, which ultimately cause peroxidative damage to vital cell structures. Because of its virtual insolubility and potential toxicity, iron must be constantly chaperoned; specialized mechanisms and molecules for the acquisition, transport, and storage of iron in a soluble, nontoxic form have evolved to meet the iron requirements of cells and organisms. Moreover, organisms are equipped with sophisticated mechanisms that prevent the accumulation of a catalytically active intracellular iron pool, while maintaining sufficient concentrations of the metal for metabolic use (Harrison and Arosio, 1996; Richardson and Ponka, 1997; Ponka et al., 1998; Aisen et al., 2001; Eaton and Qian, 2002; Hentze et al., 2004; Andrews, 2005; Hentze et al., 2010; Sheftel et al., 2012).
Iron, both in its heme and nonheme forms, is present in every cell in the body; most cells, except for mature red cells and terminally differentiated lens epithelium, have the capacity to acquire iron. However, cellular iron acquisition and its proper intracellular targeting into functional iron proteins depend on an array of other proteins. “Traditional” proteins involved in iron metabolism include transferrin, transferrin receptor, and ferritin, but a remarkable flurry of activity since the 1990s has identified a large number of novel genes whose products have emerged as important players in iron metabolism (Table 1).
TABLE 1. Some Proteins Involved in Iron Metabolism
| Protein | Function | Result of deficiency | Reference(s) |
|---|---|---|---|
| ABCB7 | Involved in Fe-S biosynthesis | XLSA with ataxia | Lill and Muhlenhoff, 2005; Napier et al., 2005 |
| ABCB10 (ABC-me) | Mitochondrial transport function related to heme synthesis; interacts with mitoferrin-1 and enhances its stability in erythroid cells | Nearly complete eradication of primitive erythropoiesis at day E 10.5; death at day 12.5 of gestation | Shirihai et al., 2000; Chen et al., 2009; Hyde et al., 2012 |
| ALA-S2/eALA-S | First enzyme of heme synthesis; erythroid-specific 5-aminolevulinic acid synthase | X-linked sideroblastic anemia | Cox et al., 1991; Fitzsimons and May, 1996; Ponka, 1997 |
| Bone morphogenic proteins 2/4/6 (BMP 2/4/6) | Positive regulator of hepcidin | Iron overload (for BMP-6) | Babitt et al., 2006, 2007; Kautz et al., 2008; Andriopoulos et al., 2009 |
| Ceruloplasmin (Cp) | Ferroxidase; involved in promoting release of Fe from cells | Neurodegeneration; iron loading of brain and liver; microcytic anemia | Hellman et al., 2002; Sheftel et al., 2012 |
| NRAMP2/DMT-1 | Membrane transporter for Fe2+ | Hypochromic microcytic anemia | Fleming et al., 1997; Gunshin et al., 1997; Mims et al., 2005; Hentze et al., 2010 |
| Cytochrome b reductase 1/duodenal cytochrome b (Dcytb) | Ferric reductase | No noticeable defect | McKie et al., 2001; Gunshin et al., 2005 |
| Ferritin (H and L) | Cellular Fe storage | H, embryonic lethality; L, unknown | Harrison and Arosio, 1996; Richardson and Ponka, 1997; Ferreira et al., 2000; Arosio et al., 2009 |
| Ferrochelatase | The last enzyme of heme synthesis; inserts Fe2+ into protoporphyrin IX | Erythropoietic protoporphyria | Cox, 1997; Ponka, 1997; Ajioka et al., 2006 |
| Ferroportin/MTP1/Ireg1 | Fe export from cells | Hemochromatosis type IV (Ferroportin disease) | Donovan et al., 2000; Pietrangelo, 2004a; Hentze et al., 2010 |
| Frataxin | Fe-binding chaperone for Fe-S cluster synthesis | Friedreich ataxia | Gerber et al., 2003; Lill and Muhlenhoff, 2005; Napier et al., 2005; Li et al., 2008; Huang et al., 2009; Sheftel and Lill, 2009; Sheftel et al., 2010 |
| Hereditary hemochromatosis protein (HLA-H/HFE) | Binds TfR; restricted expression (enterocytes, macrophages); regulates interaction of Tf with TfR1/TfR2 | Hemochromatosis type I (variable penetrance) | Feder et al., 1996; Pietrangelo, 2004; Fleming and Ponka, 2012; Sheftel et al., 2012 |
| Heme oxygenase 1 (HO-1) | Catalyzes the release of iron from protoporphyrin IX; involved in the recycling of hemoglobin Fe | Severe anemia and inflammation | Yachie et al., 1999; Maines, 2004; Maines and Gibbs, 2005; Abraham and Kappas, 2008 |
| Hemojuvelin (HJV/HFE2/RGMc) | Coreceptor for BMP-2 and 4; binds neogenin | Juvenile hemochromatosis (subtype of type II) | Papanikolaou et al., 2004; Babitt et al., 2007; Zhang et al., 2008 |
| Hepcidin | Negative regulator of iron absorption and iron release from macrophages; causes the internalization and degradation of ferroportin | Juvenile hemochromatosis (subtype of type II); overexpression of hepcidin causes severe Fe deficiency anemia | Park et al., 2001; Nicolas et al., 2002; Nemeth et al., 2004; Ganz 2005, 2011; Fleming and Ponka, 2012; Sheftel et al., 2012 |
| Hephaestin | Regulation of Fe export from enterocytes (membrane-bound Cp homolog) | Hypochromic microcytic anemia (sex-linked anemia in mice) | Vulpe et al., 1999; Sheftel et al., 2012 |
| Iron regulatory proteins (IRP 1 and 2) | Fe “sensors”; bind to IREs | IRP1, Elevated ferritin in brown fat and kidney; IRP2, microcytic anemia, erythropoietic protoporphyria, neurodegeneration | Richardson and Ponka, 1997; Mikulits et al., 1999; Pantopoulos, 2004; Cooperman et al., 2005; Meyron-Holtz et al., 2004; Hentze et al., 2010; Sheftel et al., 2012 |
| Huntingtin | Transferrin receptor trafficking | Huntingtin knockout zebrafish have microcytic anemia | Hilditch-Maguire et al., 2000; Lumsden et al., 2007 |
| Melanotransferrin | Unknown | Unknown | Richardson and Ponka, 1997; Suryo Rahmanto et al., 2012 |
| Mitochondrial ferritin | Mitochondrial Fe storage (?) | Unknown; high expression in “ring” sideroblasts | Levi et al., 2001; Napier et al., 2005; Nie et al., 2005; Richardson et al., 2010; Sheftel et al., 2012 |
| Mitoferrin-1 (erythroid specific), Mitoferrin-2 (ubiquitous) | Involved in mitochondrial iron delivery | Mitoferrin-1, Hypochromic, microcytic anemia; erythroid maturation arrest | Shaw et al., 2006 |
| Sec15l1 | “Vesicle docking” | “Hemoglobin-deficit” (hbd) mice | Lim et al., 2005; White et al., 2005; Zhang et al., 2006 |
| Sideroflexin 1 | Mitochondrial transport function related to Fe metabolism | Siderocytic anemia (mice) | Fleming et al., 2001 |
| Steap3 (six-transmembrane epithelial antigen of the prostate 3) | Endosomal ferrireductase | Hypochromic anemia (mice) | Ohgami et al., 2005 |
| Matriptase-2 (TMPRSS6) | Serine protease regulating the processing of hepcidin | Microcytic anemia | Du et al., 2008; Finberg et al., 2008 |
| Transferrin (Tf) | Fe(III)-carrier in plasma | Severe anemia (iron unavailable for erythropoiesis; iron overload | Richardson and Ponka, 1997; Ponka, 2002 |
| Tf receptor (TfR) | Membrane receptor for Fe2-Tf | Embryonic lethality | Richardson and Ponka, 1997; Levy et al., 1999; Ponka et al., 1999; Aisen, 2004; Sheftel et al., 2012 |
| TfR2 | Required for the regulation of hepcidin | Hemochromatosis type III | Kawabata et al., 1999; Camaschella et al., 2000; Chen and Enns, 2012 |
| ZIP14 | Putative mediator of non-Tf-bound iron uptake in hepatocytes | Unknown | Liuzzi et al., 2006 |
IRE, iron-responsive element; XLSA, X-linked sideroblastic anemia.
The bodies of adult men and women contain 55 mg and 45 mg of iron per kilogram body weight, respectively. Normally, 70-80% of total body iron is present in hemoglobin in circulating erythrocytes. In vertebrates, iron is transported within the body between sites of absorption, storage, and utilization by the plasma glycoprotein transferrin, which binds iron(III) very tightly but reversibly. The turnover of transferrin iron is roughly 30 mg/24 h; normally, about 80% of this iron is transported to the bone marrow for hemoglobin synthesis in developing erythroid cells. Senescent erythrocytes are phagocytosed by macrophages of the reticuloendothelial system; the heme moiety is then split from hemoglobin and catabolized enzymatically via heme oxygenase 1 (HO-1). Most of the iron that is liberated from its confinement within the tetrapyrrole ring inside macrophages is returned to the circulation. The remaining 5 mg of the daily plasma iron turnover is exchanged with nonerythroid tissues, primarily the liver. About 1 mg of dietary iron is absorbed per 24 h and the total iron balance is maintained by a daily loss of 1 mg via nonspecific mechanisms (mostly cell desquamation) (Ponka et al., 1998; Ponka, 2003; Andrews, 2005; Fleming and Ponka, 2012). This process represents an extraordinarily delicate balancing act, given that iron amounts to about 1/100,000,000th part (weight/weight) of the human body.
5.2 Cellular Iron Acquisition from Transferrin
With some notable exceptions (e.g. enterocytes), virtually all the cells in the organism take up iron from transferrin. Delivery of iron to cells occurs following the binding of transferrin to its cognate receptors on the cell membrane (reviewed in Richardson and Ponka, 1997; Ponka and Lok, 1999; Hentze et al., 2004; Sheftel et al., 2012). The transferrin-receptor complexes are then internalized by endocytosis, and iron is released from transferrin by a process involving endosomal acidification (Figure 1). It has been shown that NRAMP2/DMT-1 is responsible for the egress of iron from the endosome (Fleming et al., 1997; Gunshin et al., 1997; Canonne-Hergaux et al., 2001). The protein is encoded by a gene that belongs to the Nramp family of genes identified by Gros and coworkers (Cellier et al., 1995). Mutations of one family member (currently known as Nramp1; expressed only in phagocytic cells) were found to predispose organisms to diseases (such as leprosy and tuberculosis) caused by intracellular pathogens. Interestingly, Nramp2 (expressed ubiquitously) generates two alternatively spliced mRNAs that differ at their 3′ untranslated regions (UTRs) by the presence or absence of an IRE (discussed below); these two forms encode proteins with distinct carboxy termini (Canonne-Hergaux et al., 1999, 2001). In collaboration with Dr Philippe Gros, we found that isoform II (derived from the non-IRE-containing mRNA) is the major DMT-1 protein isoform expressed in developing erythroid cells (Canonne-Hergaux et al., 2001). One of us (Ponka) was a member of the team who identified the first human SLC11A2 mutation, causing severe hypochromic microcytic anemia (Priwitzerova et al., 2004, 2005; Mims et al., 2005). Since the form of iron bound to transferrin is in the +3 oxidation state, a reduction step, probably catalyzed by metalloreductase STEAP3 (Ohgami et al.,2005) or another member of the STEAP family (Ohgami et al., 2006), is required for transport out of the endosome.
FIGURE 1. Schematic representation of iron uptake from transferrin (Tf) via Tf receptor (TfR)-mediated endocytosis in mammalian cells.
Extracellular Fe23+-Tf is bound by the membrane-bound TfR and internalized via receptor-mediated endocytosis into an endosome. Iron is released from transferrin within endosomes by a combination of Fe3+ reduction by Steap3 (probably when it is still bound to TfR) (Dhungana et al., 2004) and decreased pH (∼pH 5.5); following this, Fe2+ is transported across the endosomal membrane by DMT-1. Physiologically, all iron in the circulation is Tf-bound and, therefore, DMT-1 expressed at the plasma membrane of erythroid and perhaps other cells has no substrate. Obviously, DMT-1 can assume its function of Fe2+ transporter only following its recruitment into endosomes where it colocalizes with TfR (Canonne-Hergaux et al., 2001). Since reticulocytes acquire Fe2+ at rates that are much higher than those of iron uptake from Fe2-Tf (Sheftel et al., 2007), DMT-1 is not a limiting factor in iron uptake via a Tf-dependent pathway in these cells. Once the iron has passed through the membrane, it then enters a very poorly characterized compartment known as the intracellular labile iron pool (LIP); however, developing erythroid cells may deliver the metal directly from Tf-containing vesicles to mitochondria (Zhang et al., 2005; Sheftel et al., 2007). Apotransferrin remains bound to the TfR and is then released by exocytosis. Iron that enters the cell can be used for metabolic functions or can be stored in ferritin. It is thought that iron in the intracellular iron pool modulates the activity of iron regulatory proteins 1 and 2 (IRP1 and IRP2).
Following its escape from endosomes, iron is transported to its intracellular sites of use and/or storage in ferritin, but much about this aspect of iron metabolism—including the nature of the elusive intermediary pool of iron and its cellular trafficking—remains unknown. Of interest, in hemoglobin-synthesizing cells, iron is specifically targeted toward mitochondria, which continue to take up the metal with a gluttonous appetite even when the synthesis of protoporphyrin IX is suppressed (reviewed in Ponka, 1997; Napier et al., 2005). In contrast, in nonerythroid cells, iron in excess of metabolic needs ends up in ferritin (Arosio et al., 2009). Hence, some specific mechanisms and controls are involved in the transport of iron into mitochondria in erythroid cells, but the nature of these processes, besides the likely role of erythroid-specific mitoferrin (see below), is unknown. Based on the fact that transferrin-bound iron is extremely efficiently used for hemoglobin synthesis, that iron is targeted into erythroid mitochondria, and that no cytoplasmic iron transport intermediate can be identified in erythroid cells, an unconventional hypothesis of intracellular iron transport has been proposed (Richardson et al., 1996; Ponka, 1997; Zhang et al., 2005; Sheftel et al., 2007). This model suggests that after iron is released from transferrin in the endosome, it is passed directly from protein to protein until it reaches ferrochelatase in the mitochondrion (a “kiss-and-run” hypothesis). Such a transfer would bypass the cytosol, as the transfer of iron between proteins could be mediated by the direct interaction of the endosome with the mitochondrion. Several reports have provided strong experimental evidence supporting this hypothesis: (1) iron delivered to mitochondria via the transferrin-receptor pathway is unavailable to cytoplasmic chelators; (2) transferrin-containing endosomes move to and contact mitochondria in erythroid cells; (3) endosomal movement is required for iron delivery to mitochondria. It was also demonstrated that “free” cytoplasmic iron is not efficiently used for heme biosynthesis and that the endosome-mitochondrion interaction increases chelatable mitochondrial iron (reviewed in Sheftel et al., 2012). Since the majority of cellular iron is processed in the mitochondria of all cells, and not just red blood cells, it is tempting to speculate that this direct interorganellar iron transport mechanism is ubiquitous.
In erythroid cells, when iron reaches the outer mitochondrial membrane, it is trapped by an as yet unidentified ligand and transferred across the inner membrane to ferrochelatase. Paw and coworkers recently demonstrated that mitoferrins are responsible for iron import, probably in its Fe2+ form, through the mitochondrial inner membrane (Shaw et al., 2006; Paradkar et al., 2009). Mitoferrin-1 exerts its function primarily in erythroid cells, but mitoferrin-2, which is expressed ubiquitously, cannot support hemoglobinization (Paradkar et al., 2009). Of considerable interest in this context is the recent discovery (Chen et al., 2010) that mitoferrin-1 physically interacts with ferrochelatase and mitochondrial ATP-binding cassette subfamily B member 10 (ABCB10), a mitochondrial inner membrane transporter highly induced during erythroid maturation (Shirihai et al., 2000). The occurrence of a mitoferrin-1-ferrochelatase complex supports the notion that erythroid iron transport consists of a relay of the metal from protein to protein, rather than simply transport of the “free” metal across membranes.
5.3 Iron Export from Cells to Transferrin
There are specialized mammalian cells that must export iron. Absorption of dietary iron for transfer to transferrin in plasma requires iron efflux across the basolateral surface of the intestinal epithelia. A second major site of iron release is from macrophages, where senescent or damaged red cells are degraded to export the metal from hemoglobin and provide it for binding to transferrin. Moreover, iron delivery to brain, placenta, and testis requires transport into and across endothelial cells (Richardson and Ponka, 1997; Ponka, 2004).
Since the early 2000s, our understanding of iron release from “donor cells” (primarily enterocytes and macrophages) to plasma transferrin has been dramatically enhanced by several seminal discoveries. It is now generally accepted that iron is exported from cells via solute carrier family 40 member 1/ferroportin (Donovan et al., 2000), also known as MTP1 (Abboud and Hailey, 2000) or Ireg1 (McKie et al., 2000). The ferroxidase activities of hephaestin (named after the Greek god of fire and iron, Hephaestus) (Vulpe et al., 1999; Anderson et al., 2002) and ceruloplasmin (after the Latin caeruleus for blue, the color of the purified protein) (Hellman and Gitlin, 2002) facilitate the movement of iron across the membranes of enterocytes and macrophages, respectively. Ceruloplasmin and hephaestin exhibit a high degree of homology, and both proteins contain several copper atoms that are necessary for their ferroxidase [i.e. oxidation of Fe(II) to Fe(III)] activity.
The next landmark discovery was the identification of hepcidin, a 25-amino-acid peptide, by three groups investigating either novel antimicrobial peptides (Krause et al., 2000; Park et al., 2001) or the high expression of this protein is during iron overload (Pigeon et al., 2001). Tomáš Ganz and his coworkers, who discovered this peptide to be associated with inflammation, named it hepcidin after observing that it was produced in the liver (i.e. hep-) and seems to have bactericidal properties. Compelling links between hepcidin and iron metabolism were presented in a report that mice that are unable to express hepcidin develop iron overload associated with decreased iron in macrophages (Nicolas et al., 2001, 2002), whereas animals that overexpress hepcidin develop lethal iron-deficiency anemia (Nicolas et al., 2002). Subsequent research revealed that hepcidin limits iron entry into the plasma from macrophages, intestinal enterocytes, and other cells. The molecular mechanism of this phenomenon involves the binding of hepcidin to the sole iron-export protein, ferroportin, and facilitating its degradation (Nemeth et al., 2004). Hence, hepcidin regulates iron entry into the circulation by promoting ferroportin destruction. Additional research revealed that iron stores and inflammation positively regulate hepcidin levels, whereas hypoxia (see below) and increased erythropoiesis downregulate the hormone’s expression (reviewed in Ganz, 2005, 2011). Of interest in this context is a report (Tanno et al., 2007) showing that the bone morphogenetic protein family member, growth/differentiation factor (GDF-15), which is released by erythroid precursors during ineffective erythropoiesis, may contribute to the pathological suppression of hepcidin seen in β-thalassemia. The unusually active research effort by investigators scattered all over the world has revealed hepcidin to be a “master regulator” of organismal iron homeostasis (reviewed in Ganz, 2005, 2011; Nemeth and Ganz, 2006, 2009).
5.4 Recycling of Hemoglobin Iron
At the end of an erythrocyte’s life, it is phagocytosed by macrophages of the reticuloendothelial system (e.g. Kupffer cells of the liver), and iron is liberated from the vice-like grip of the protoporphyrin ring by HO-1) (Maines, 2004; Maines and Gibbs, 2005). Organelles containing engulfed senescent or pathological erythrocytes are believed to merge with lysosomes, leading to the formation of erythrophagolysosomes. It is here that the globin moiety of hemoglobin is likely to be degraded, but the fate of heme, which has to undergo HO-1-mediated degradation, is unknown. Most of the comments on this phenomenon implicitly or explicitly indicate that heme is somehow moved toward the endoplasmic reticulum that allegedly harbors HO-1. However, no heme exporter from erythrophagolysosomes has ever been identified. There is an alternative possibility, i.e. that following erythrophagocytosis, HO-1 confined to vesicularized ER is recruited by erythrophagolysosomes. This view is supported by recent observations that both NRAMP1 (a homolog of DMT-1, which also transports divalent metals) (Forbes and Gros, 2003) and DMT-1 are involved in the export of hemoglobin-derived iron from macrophages (Soe-Lin et al., 2008, 2009, 2010). This observation suggests that it is not heme, but is instead the iron liberated from it, that is released from the erythrophagolysosome. Macrophages have an enormous capacity to purge themselves of iron, which is exported via ferroportin (Figure 2). Under normal circumstances, during the same period these cells simultaneously convey to plasma the same amount of iron that is delivered from transferrin to developing erythroid cells.
FIGURE 2. Scheme of possible iron pathways in reticuloendothelial macrophages involved in the recycling of hemoglobin iron.
Following phagocytosis of senescent red blood cells, the erythrocyte membrane is lysed and heme is allegedly transported to the endoplasmic reticulum (E.R.) to be degraded by heme oxygenase 1 (HO-1). Most of the iron derived from hemoglobin catabolism is promptly returned to the circulation, probably being transported across the plasma membrane by solute carrier family 40 member 1/ferroportin-1. In Kupffer cells, ferroportin (MTP1, Ireg1) is present in not only at the plasma membrane but also in the cytoplasm (Abboud and Hailey, 2000).
5.5 Iron Absorption
No information is available to allow the assessment of iron acquisition by the organism via inhalation. General knowledge on the uptake of airborne particles is summarized in Chapter 3. Normally, the body iron content in humans is maintained within narrow limits by the regulation of intestinal iron absorption (Miret et al., 2003). Both heme and elemental iron are absorbed through the brush border of the upper small intestine. Heme iron is more readily available for absorption, but usually constitutes only a small fraction of dietary iron. Heme (derived from hemoglobin or myoglobin) is taken up intact, probably via specific high-affinity heme-binding sites in the mucosal brush border (Figure 3) (Grasbeck et al., 1982; Worthington et al., 2001; Shayeghi et al., 2005). After entering intestinal epithelial cells, iron is enzymatically released from heme by HO-1.
FIGURE 3. Iron transport across the intestinal epithelium.
Iron must cross two membranes to be transferred across the absorptive epithelium. The apical transporter has been identified as DMT-1. It acts in concert with cytochrome b reductase 1/duodenal cytochrome b (Dcytb), which supposedly reduces ferric iron to more malleable Fe2+ ions. The basolateral transporter, ferroportin, requires ferroxidase activity of hephaestin (ceruloplasmin-like molecule) for the transfer of iron to the plasma. Hephaestin is depicted here at the basolateral surface of the cell, but it is not known whether it functions at this location. Heme iron is taken up by a separate process that is not well characterized. Excess iron within enterocytes is stored as ferritin. LIP, labile iron pool. ApoTf, apotransferrin.
As previously mentioned, elemental Fe(III) is virtually insoluble at neutral pH; therefore, the availability of dietary iron for intestinal absorption depends on the composition of intestinal secretions, as well as on ligands and reducing agents present in the diet. Ascorbic acid is the most powerful promoter of nonheme iron absorption, which is also enhanced by organic acids (e.g. citric acid and amino acids). On the other hand, compounds that form insoluble complexes with iron (e.g. phosphates, phytates, and tannin) prevent absorption. Similarly, conditions in which there is a failure of gastric acid secretion (e.g. atrophic gastritis) may significantly reduce the availability of iron for absorption (Miret et al., 2003).
The process of inorganic iron absorption is not fully understood, but a compelling candidate iron transporter has recently been identified. DMT-1, which is involved in iron transport across the endosomal membrane (see above), is also a principal transporter of iron in the intestine (Gunshin et al., 1997; Canonne-Hergaux et al., 1999). DMT-1 transports only the ferrous (reduced) form of iron, which explains why reducing agents enhance iron absorption. Moreover, the duodenal brush border contains a ferric reductase, Dcytb (McKie et al., 2001), that has been proposed to play a role in the formation of Fe(II) prior to its transport into the enterocyte. However, recently, Andrews and coworkers inactivated the murine Dcytb gene and showed that Dcytb deficiency did not impair intestinal iron absorption when mice were fed normal chow (Gunshin et al., 2005). Hence, Dcytb does not seem to be an essential component of the intestinal iron absorption system in mice. The chemical nature of iron in the labile intermediate pool in enterocytes is unknown, but a protein necessary for iron egress from enterocytes was recently identified. This protein, ferroportin (Donovan et al., 2000; Abboud and Hailey, 2000; McKie et al., 2000), is identical to the Fe(II) exporter involved in iron egress from macrophages (see Figure 2). The ferroxidase activity of hephaestin (Vulpe et al., 1999; Anderson et al., 2002), a membrane-bound ceruloplasmin homolog, also plays an important role in iron export from intestinal epithelial cells to the circulation (Hellman and Gitlin, 2002). Hephaestin is not an iron transporter itself, but probably interacts with the ferroportin to facilitate the movement of iron across the membrane (Figure 3). Hephaestin is mutated in sex-linked anemic (sla/sla) mice that take up iron from the intestinal lumen into the epithelial cells normally, but the subsequent exit of iron into the circulation is diminished (Vulpe et al., 1999). It is of interest that during the process of absorption, iron undergoes at least two changes in its oxidation status: reduction at the brush border and oxidation at the basolateral membrane.
Physiologically, the two major factors affecting iron absorption are the amount of body iron stores and the rate of erythropoiesis (Miret et al., 2003). The uptake of iron by mucosal cells is inversely proportional to total body iron content but seems to be independent of changes in plasma iron or transferrin concentration. The 3′ UTR of SLC11A2 mRNA expressed in intestinal cells contains IRE (Canonne-Hergeaux et al., 1999); hence, based on the IRE/IRP paradigm (see below), diminished iron levels would be expected to increase DMT-1 expression and vice versa. It is unclear how increased erythropoietic activity (increased plasma iron turnover?) enhances iron absorption. Hypoxia can directly stimulate iron absorption, independent of changes in erythroid activity. Interestingly, the SLC11A2 gene contains regulatory elements responsible for its increased transcription under hypoxic conditions (Lee et al., 1998). Hepcidin expression can also be reduced by hypoxia (see below), which is expected to increase iron absorption.
5.6 Control of Cellular Iron Homeostasis
Cells are equipped with a remarkable regulatory system that tightly controls iron levels in the “labile iron pool” (LIP), presumably representing iron in transit among various intracellular compartments. Sensitive control mechanisms exist that monitor iron levels in the LIP and prevent its expansion, while still making the metal available for iron-dependent proteins and enzymes. In general, enlargement of the LIP leads to stimulation of ferritin synthesis and a decrease in the expression of transferrin receptors, but the opposite occurs when this pool is depleted. Pivotal players in this regulatory mechanism are IRP1 and IRP2, which “sense” iron levels in the LIP.
Iron-dependent regulation of both ferritin and transferrin receptors occurs posttranscriptionally (i.e. it does not involve mRNA synthesis) and is mediated by virtually identical IREs. IREs present in the 5′ UTRs of mRNAs encoding e.g. ferritin and erythroid-specific mitochondrial 5-aminolevulate synthase (ALAS-E, the first enzyme of heme biosynthesis; encoded by ALAS2) mediate inhibition of translation of the respective mRNAs in iron-deprived cells. Five similar IREs (versus a single IRE in ferritin and ALAS2 mRNAs) are also present in the 3′ UTR of transferrin receptor mRNAs. These IREs increase the stability of transferrin receptor mRNAs as a function of cellular iron levels. The IREs are nucleotide sequences that are recognized by specific cytosolic RNA-binding proteins known as IRP1 and IRP2. An IRE-binding form of each IRP accumulates in iron-depleted cells, but the mechanism of accumulation differs. When cellular iron is low, IRP1 is in a form that can bind to IREs, and IRP2 (which has constitutive RNA-binding activity) is stable. Binding of IRPs to IREs within the 5′ end of mRNA (ferritin, ALAS2) inhibits translation of these transcripts, whereas binding to IREs in the 3′ UTR of the TfR (and probably also in the intestinal form of SLC11A2 mRNA) stabilizes the transcripts. Hence, iron deficiency promotes cellular iron acquisition and possibly intestinal iron absorption, while it decreases levels of the cellular iron-storing protein, ferritin. On the other hand, expansion of the LIP inactivates IRP1 binding and leads to degradation of IRP2, resulting in efficient translation of ferritin mRNA (and ALAS2 mRNA in erythroid cells) and rapid degradation of transferrin receptor mRNAs (reviewed in Richardson and Ponka, 1997; Rouault and Klausner, 1997; Mikulits et al., 1999; Hentze et al., 2004; Wang and Pantopoulos, 2011).
Some cells and tissues with specific requirements for iron have probably evolved mechanisms that can override IRE/IRP-dependent control of transferrin receptor formation. Erythroid cells, which are the most avid consumers of iron in organisms, use a transcriptional mechanism (i.e. they actively synthesize receptor mRNA) to maintain very high transferrin receptor levels (Ponka, 1997; Lok and Ponka, 2000). Moreover, erythroid cells are equipped with an important regulatory mechanism that coordinates protoporphyrin IX formation with iron supply (Ponka, 1997). Because the 5′ UTR of ALAS2 mRNA contains the IRE (Cox et al., 1991; Dandekar et al., 1991; Melefors et al., 1993), the formation of ALAS-E (the rate-limiting enzyme for porphyrin biosynthesis) and, consequently, of protoporphyrin IX depends on the availability of iron.
Although the IRE/IRP system has probably evolved to sense iron in transit and to maintain it at appropriate levels, iron is not the only factor that modulates IRPs. Recently, nitric oxide (NO) and oxidative stress were shown to dramatically affect the binding of IRPs to IREs and, consequently, cellular iron metabolism (Pantopoulos and Hentze, 1995; Hentze and Kühn, 1996; Pantopoulos et al., 1996; Kim and Ponka, 1999, 2000, 2002a,b). We should note, however, that this type of IRE/IRP system modulation may also involve indirect, oxidant-mediated changes in intracellular iron availability. As will be discussed later, NO-mediated changes in iron metabolism in “inflammatory” macrophages provide important clues to the pathogenesis of anemia of chronic disease.
URL: https://www.sciencedirect.com/science/article/pii/B978044459453200041X
Iron metabolism and regulatory networks
Iron is essential to sustain life. As a transition metal, iron is highly flexible in oxidation states and plays a versatile role in redox reactions and electron transport to regulate psychological actions, such as DNA synthesis and repair, energy metabolism, and oxygen transport [1]. Iron metabolism is composed of iron uptake, storage, and efflux, which work together to maintain intracellular iron homeostasis [2] (Figure 1). In the classic iron uptake system, iron frequently binds to transferrin (TF), the most ubiquitous iron binding carrier protein, and is conveyed to target cells via transferrin receptor protein 1 (TFR1, encoded by TFRC)-mediated endocytosis [1,3]. Once the TF-Fe-TFR1 complex enters cells, iron is released from transferrin as Fe(II) by the catalysis of six-transmembrane epithelial antigen of prostate 3 (STEAP3) in acidified endolysosomes and is subsequently transported into the cytoplasm via the transporter divalent metal transporter (DMT1). In addition, lipocalin-2 (LCN2)/SLC22A17, hyaluronate/cluster determinant 44 (CD44) and non–transferrin-bound iron (NTBI) all have been reported to be involved in iron uptake [4–8]. Meanwhile, to isolate excess iron and increase the regulatory flexibility of iron metabolism, excess free iron that is not used in biological processes is stored as Fe(III) in ferritin in a nonreactive form [9,10]. Iron efflux is regulated mainly through ferroportin (FPN); meanwhile, iron-loaded ferritin can also be expelled out of the cell by formation of exosomes in a cluster determinant 63 (CD63)- or prominin 2 (PROM2)-dependent manner [11–15]. Cancer cells frequently reprogram their iron metabolism to meet the increased demands for iron to support energy and biosynthesis. Previous studies have shown that TFR1 is upregulated and correlates with poor prognosis in a wide variety of tumors, including breast cancer [16], leukemia [17], endometrial carcinoma and cervical cancer [18]. In contrast, to retain intracellular iron, cancer cells usually have a decrease of FPN levels in multiple cancer types [13,19]. Moreover, iron homeostasis can also be impacted by oncogenes. A recent paper reported that oncogenic KRAS signaling mediated ferrous iron accumulation by inducing elevation of STEAP3 expression and reduction of FPN in pancreatic ductal adenocarcinoma [20]. This iron dependency elicits the possibility to selectively kill cancer cells via chelating iron by iron chelators.
Figure 1. The cellular iron homeostasis handling machinery.
Cellular iron homeostasis is maintained by various processes, including iron uptake, utilization, storage, and efflux. Classically, extracellular iron can be acquired through TF-TFR1, LCN2-SLC22A17, and CD44-mediated endocytosis [4,5,8]. Following endocytosis, the carrier-bound iron dissociates in the acidic endolysosomal compartment and is converted to ferric by STEAP3. Subsequently, the ferric iron is transferred into the cytoplasm through DMT1 [1]. In parallel, non–transferrin-bound iron (NTBI) is transported directly into the cytoplasm via transmembrane ion channels ZIP8 and ZIP14 to fuel the LIP [6,7]. A key role of iron in the LIP is to participate in the synthesis of iron-sulfur clusters (ISCs) and heme, which are critical cofactors of numerous proteins in the electron transport chain (ETC) and tricarboxylic acid (TCA) cycle in the mitochondrial matrix [1,96]. Excess iron is stored in ferritin and can be mobilized through the NCOA4-mediated ferritinophagy during iron deficiency or exported outside the cell via ferroportin (FPN). This export is suppressed by hepcidin, an iron-regulatory hormone secreted by hepatocytes [13,76]. Moreover, iron-loaded ferritin can be secreted in the exosome through PROM2- or CD63-mediated iron export [14,15]. Abbreviations: DMT1, divalent metal transporter 1; ETC, electron transport chain; LCN2, lipocalin-2; LIP, labile iron pool; NCOA4, nuclear receptor coactivator 4; NTBI, non-transferrin-bound iron; PROM2, prominin 2; STEAP3, six-transmembrane epithelial antigen of prostate 3; TCA, tricarboxylic acid cycle; TF, transferrin; TFR1, transferrin receptor protein 1; ZIP8/ZIP14, Zrt- and Irt-like proteins 8/14.
However, iron is also potentially toxic by inducing iron-mediated oxidative cell damage and ferroptosis (Box 1), an iron-dependent form of nonapoptotic cell death [21]. Therefore, cells orchestrate a finely tuned system, navigating iron uptake, storage, and efflux to maintain intracellular iron homeostasis. Generally, iron is principally regulated at both the systemic and intracellular levels by the hepcidin-ferroportin axis or the iron regulatory protein (IRP)–iron responsive elements (IRE) regulatory system, respectively [1] (Figure 2 and Box 2). Maintaining iron homeostasis is critical in both tumor and immune cells. Although the role of iron in tumor cells has been widely studied, recent studies have uncovered the interplay of iron metabolism between tumor cells and immune cells, which may affect both innate and adaptive immune responses [5,22–27]. In this review, we discuss the current understanding of the regulatory networks of iron metabolism between cancer cells and immune cells and how they contribute to antitumor immunity, and we analyze potential therapeutics targeting iron metabolism. We highlight several key challenges and describe potential therapeutic approaches for future investigations.
Box 1
Regulation of systemic and cellular iron homeostasis
The hepcidin–ferroportin axis
Systemic iron homeostasis in the body is controlled by the hepcidin–ferroportin (FPN) axis to make sure that cells can retain enough iron for biological processes. When serum iron concentrations are high or in response to immune activation, hepcidin is secreted into the blood circulation. Subsequently, hepcidin blocks the efflux of iron into the serum from iron-exporting cells by binding to the iron export transporter FPN and then triggering its degradation [3,74,75]. The hepcidin-ferroportin axis also acts locally in the tumor microenvironment to help cancer cells maintain sufficient iron to support cancer progression [76].
IRP-IRE–mediated iron regulatory network
Classically, intracellular iron homeostasis is coordinated by a post-translational system including iron regulatory protein IRP1 (also known as ACO1), IRP2 (also known as IREB2), and cis-regulatory IREs with a stem loop structure located in the untranslated region (UTR) of mRNAs encoding key proteins of iron metabolism. When iron is deficient, active IRPs can bind to the 5′-UTR IRE of mRNAs with high affinity, which encode a series of proteins that can decrease intracellular iron and inhibit their translation, such as iron storage proteins ferritin heavy chain (FTH) and ferritin light chain (FTL), iron exporter ferroportin, and erythroid aminolevulinate synthase (ALAS2). At the same time, IRP also interacts with the 3′-UTR IREs of mRNAs encoding proteins in favor of iron accumulation and promotes the stability of these mRNAs. For instance, IRP combines with the 3′-UTR IREs of TFRC mRNA under iron deprivation and protects its transcript from digestion by the Regnase-1 (ZC3H12A) and Roquin-1 (RC3H1) nucleases, increasing TFR1 protein synthesis and then promoting iron uptake [77,78]. Conversely, in iron- and oxygen-replete cells, IRP-1 incorporates an ISC, converting it to a form that is unable to bind to IREs [1], whereas IRP-2 is displaced from IRE RNA by F-box and leucine-rich repeat protein 5 (FBXL5) and is targeted for rapid degradation [79].
Figure 2. The IRP–IRE regulatory network and hepcidin–ferroportin axis.
At the cellular level, the apo-IRP1 or active IRP2 can bind to IREs in the 3′ or 5′ untranslated region (UTR) of the target mRNA and either prevents mRNA degradation (such as TFR1) or inhibits mRNA translation (such as FTH, FTL, ferroportin) to ultimately support the maintenance of intracellular iron in the context of iron deprivation [77,78]. Conversely, in iron-rich cells, IRP1 loses its IRE-binding activity by incorporating an iron-sulfur cluster and functions as a cytosolic aconitase, whereas IRP-2 is rapidly degraded [79]. As a result, intracellular concentration of free iron can be restricted. Systemically, hepcidin secreted by the liver can reduce the release of ferrous iron into the plasma from iron-exporting cells by binding to and promoting the degradation of ferroportin in response to immune activation or high systemic iron levels [3,74,75]. Abbreviations: ACO1, aconitase 1; FBXL5, F-box and leucine-rich repeat protein 5; IRE, iron responsive element; IRP, iron regulatory protein; SCF E3 ligase, SKP1-CUL1-F-box E3 ligase; STEAP3, six-transmembrane epithelial antigen of prostate 3; TF, transferrin; TFR1, transferrin receptor protein 1.
Box 2
Ferroptosis
Ferroptosis is a kind of nonapoptotic form of regulated cell death that occurs through excessive peroxidation of polyunsaturated fatty acids (PUFAs) produced by an iron-dependent Fenton reaction. Correspondingly, cancer cells also well orchestrate the antioxidant systems to defend ferroptosis, including the SLC7A11-GSH-GPX4 system, the FSP1–CoQH2 system, the DHODH–CoQH2 system, and the GCH1–BH4 system [80]. Among these, the SLC7A11-GSH-GPX4 axis was first discovered and most widely studied. The enzyme glutathione peroxidase 4 (GPX4) protects cells from ferroptosis by converting lipid hydroperoxides into nontoxic lipid alcohols, with GSH serving as a reducing cosubstrate for the catalytic reaction. SLC7A11-mediated cystine uptake is a rate-limiting step for GSH synthesis, which is important in maintaining GPX4 enzyme activity. Disrupting the SLC7A11-GSH-GPX4 axis can effectively induce ferroptosis. Thus, targeting SLC7A11 by erastin and targeting GPX4 by RSL-3 are frequently used approaches to get ferroptotic cells in scientific research [81].
URL: https://www.sciencedirect.com/science/article/pii/S0165614723002614
2.1.1 Iron metabolism
Iron is one of the essential nutritional elements of organisms. It mainly exists in the form of Fe3+ in food and is absorbed in the intestinal epithelial cell [26]. In circulation, iron binds with transferrin (TF) in the form of Fe3+ and is transported through transferrin receptor 1 (TFR1) on the surface of the cell membrane. The conjugate enters the cell through an endocytosis manner [27]. In the acidic endosomal environment, Fe3+ is released from the conjugate, reduced to Fe2+ by six transmembrane epithelial antigens of prostate 3 (STEAP3), and then enters the cytoplasm from the endosome through divalent metal transporter 1 (DMT1) [28]. Excess iron is mainly stored in ferritin in the form of redox inactivity. A small amount of Fe2+ forms the labile iron pool (LIP) [29]. Fe2+ is transported to the outside of cells under the action of membrane iron transporter 1 (FPN1). Generally, the balance of iron in cells is reflected in the balance among iron absorption, output, utilization, and storage [30]. When intracellular iron is overloaded, on the one hand, the highly oxidizing free Fe2+ can easily undergo Fenton reaction with lipid peroxide, produce hydroxyl radical, arouse strong oxidative stress response, produce a large number of ROS and induce ferroptosis [31]. On the other hand, Fe2+ is a cofactor that enhances the activities of various metabolic enzymes, promotes the production of lipid ROS, and then promotes ferroptosis [28]. In conclusion, abnormal iron metabolism may increase intracellular iron, cause iron-related ROS deposition, and induce ferroptosis. Iron is an essential element of ferroptosis, and iron metabolism is a necessary process of ferroptosis.
URL: https://www.sciencedirect.com/science/article/pii/S2212877822000394
Abnormal iron metabolism has long been regarded as a key metabolic hallmark of cancer. As a critical cofactor, iron contributes to tumor progression by participating in various processes such as mitochondrial electron transport, gene regulation, and DNA synthesis or repair. Although the role of iron in tumor cells has been widely studied, recent studies have uncovered the interplay of iron metabolism between tumor cells and immune cells, which may affect both innate and adaptive immune responses. In this review, we discuss the current understanding of the regulatory networks of iron metabolism between cancer cells and immune cells and how they contribute to antitumor immunity, and we analyze potential therapeutics targeting iron metabolism. Also, we highlight several key challenges and describe potential therapeutic approaches for future investigations.
URL: https://www.sciencedirect.com/science/article/pii/S0165614723002614
Iron is essential in many physiological processes, including DNA metabolism, oxygen transport, and cellular energy generation. Deregulated iron metabolism, which results in iron overload or iron deficiency, is observed in many different diseases. We here summarize recent progress in the pathophysiology and pharmacology of iron-overload diseases, such as hereditary hemochromatosis, as well as iron-deficiency disorders, which are typically associated with anemia. The role of iron in immunity and the connection between iron and cancer are also addressed. We finally summarize and discuss the current (pre-) clinical landscape of pharmacotherapies targeting key players involved in iron metabolism.
URL: https://www.sciencedirect.com/science/article/pii/S0165614721000961
The role of iron in ferroptosis
Numerous metabolic regulatory domains, such as oxygen transport, electron transport, deoxyribonucleotide synthesis, and redox reactions involving hemoproteins and Fe-S cluster proteins, critically depend on iron availability. Deficiency or surplus of iron results from dysregulated iron homeostasis [20]. Iron metabolism plays a crucial role in the peroxidation of lipids and ferroptotic cell death by accumulating iron in cells. Deranged or excessive availability of labile intracellular iron promotes the accumulation of damaging reactive oxygen species (ROS) via the Fenton reactions with H2O2 generated during metabolic processes or other sources, including NADPH oxidase activity. This excessive ROS yield leads to uncontrolled lipid peroxidation and eventual ferroptotic cell death [13]. There have been several discoveries regarding iron metabolism, including transferrin receptor 1 (TFR1) and iron transport and uptake are performed by divalent metal transporter 1 (DMT1), intracellular iron export is carried out by ferroportin (FPN), and iron storage is accomplished by ferritin [21,22]. It is possible that iron metabolism can be disturbed, resulting in compromised iron homeostasis. Iron overload may facilitate ferroptosis by catalyzing the Fenton reaction, causing lipid peroxidation [23]. Not surprisingly, ferroptosis can be effectively suppressed using antioxidants and iron chelators.
URL: https://www.sciencedirect.com/science/article/pii/S1471489223000851
101.1 Introduction
Iron is one of the most abundant elements on earth and a vital component of the cellular processes of most living things. It is used in many enzymatic reactions, including multiple steps of the electron transport chain and the tricarboxylic acid cycle, as well as in reactions catalyzed by microsomal cytochromes involved in detoxification of drugs and other foreign substances. The majority of iron functions as oxygen carrier in the heme groups of hemoglobin and myoglobin. In large quantities and when unbound, iron can be highly toxic to cells. Much of iron metabolism involves maintaining a delicate balance between sequestered and free ion, absorption, elimination, and reutilization. Over time, seemingly small changes in this balance can cause disease. Recent advances in understanding the molecular causes of common and rare disorders of iron metabolism have revealed regulatory pathways previously unappreciated, which suggest novel therapeutic strategies.
URL: https://www.sciencedirect.com/science/article/pii/B9780123838346001063