Cellular Iron Metabolism

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Before describing in detail about the effects of NO on intracellular Fe pools, it is important to discuss the mechanisms involved in Fe metabolism. Iron is fundamental for life as it is a cofactor of enzymes such as cytochrome c and ribonucleotide reductase, which are essential for ATP production and DNA synthesis, respectively (for reviews see [11,35]).

The maintenance of mammalian iron (Fe) homeostasis begins with the ability to absorb and control dietary Fe from the gut via enterocytes (for review see [36]). Most Fe in food is ingested as the ferric form (Fe3+) and is fairly insoluble. Hence, the absorption of dietary Fe requires the reduction of the ferric state to its ferrous form and this was thought to be achieved by the Fe-regulated duodenal cytochrome b enzyme (Dcytb) [37]. However, more recent studies using Dcytb knockout mice have demonstrated that this molecule is not essential for normal Fe metabolism in the whole animal [38]. Once Fe3+ is reduced to Fe2+, it is transported into the cell by the divalent metal ion transporter 1 (DMT1; also known as the divalent cation transporter or the natural resistance associated macrophage protein 2) [39-41]. Haem can also be transported into enterocytes and recently a candidate molecule that possesses this activity [haem carrier protein 1 (HCP1)] has been described [42]. However, while this protein appears to transport haem, there is no strong evidence as yet that it is the physiologically relevant mechanism. Intriguingly, another haem transporter known as the human feline leukemia virus subgroup C receptor (FLVCR) has also been identified [43]. However, its role in haem trafficking in the intestine remains unclear.

The trafficking of Fe in the enterocyte and its subsequent release into the bloodstream remains the subject of intensive research and is only briefly discussed herein (Fig. 1).

Fig. 1. Schematic illustration of the mechanism of Fe uptake by the enterocyte. Iron is internalized after inorganic Fe3+ in the diet is reduced to Fe2+ possibly by a ferrireductase known as Dcytb. However, the identity of this ferrireductase remains controversial [38]. Haem may be taken up from the gut lumen via specific transporters, e.g. haem carrier protein 1 (HCP1) [42] and/or feline leukemia virus subgroup C receptor (FLVCR) [43]. Internalized haem is then metabolized by haem oxygenase 1 to Fe2+, bilirubin and carbon monoxide (CO). The Fe2+ probably then enters a compartment known as the intracellular Fe pool or is stored in ferritin. In a sequence of events that remains unclear, the ferroxidase hephaestin may be involved in the conversion of Fe2+ to Fe3+ and the subsequent release from the cell via ferroportin-1. The Fe efflux mediated by ferroportin-1 is thought to be Fe2+ which may then be oxidized by the ferroxidase activity of ceruloplasmin or apo-transferrin in the serum. The Fe3+ is then subsequently bound by apo-Tf to form diferric Tf. The release of Fe from the enterocyte is regulated at least to some degree by the peptide, hepcidin, which is synthesized by the liver. High levels of storage Fe in the liver or the inflammatory cytokine, interleukin-6 (IL-6), increase hepcidin expression that decreases Fe release from the enterocyte, probably by down-regulation of ferroportin-1 (see text for details). (Taken with permission from: Richardson DR. Curr. Med. Chem. 2005; 12: 2711-2729.)

Fig. 1. Schematic illustration of the mechanism of Fe uptake by the enterocyte. Iron is internalized after inorganic Fe3+ in the diet is reduced to Fe2+ possibly by a ferrireductase known as Dcytb. However, the identity of this ferrireductase remains controversial [38]. Haem may be taken up from the gut lumen via specific transporters, e.g. haem carrier protein 1 (HCP1) [42] and/or feline leukemia virus subgroup C receptor (FLVCR) [43]. Internalized haem is then metabolized by haem oxygenase 1 to Fe2+, bilirubin and carbon monoxide (CO). The Fe2+ probably then enters a compartment known as the intracellular Fe pool or is stored in ferritin. In a sequence of events that remains unclear, the ferroxidase hephaestin may be involved in the conversion of Fe2+ to Fe3+ and the subsequent release from the cell via ferroportin-1. The Fe efflux mediated by ferroportin-1 is thought to be Fe2+ which may then be oxidized by the ferroxidase activity of ceruloplasmin or apo-transferrin in the serum. The Fe3+ is then subsequently bound by apo-Tf to form diferric Tf. The release of Fe from the enterocyte is regulated at least to some degree by the peptide, hepcidin, which is synthesized by the liver. High levels of storage Fe in the liver or the inflammatory cytokine, interleukin-6 (IL-6), increase hepcidin expression that decreases Fe release from the enterocyte, probably by down-regulation of ferroportin-1 (see text for details). (Taken with permission from: Richardson DR. Curr. Med. Chem. 2005; 12: 2711-2729.)

The process involves a series of molecular events that include the function of the proteins, hephaestin and ferroportin-1 [44]. The latter molecule is also known as metal transporter protein 1 (MTP1; [45]) or Ireg1 [46]. Hephaestin is a transmembrane, multi-copper ferroxidase that has homology to the serum protein, ceruloplasmin [11,47]. By way of its ferroxidase activity, hephaestin may facilitate Fe export from intestinal enterocytes, perhaps in cooperation with the basolateral Fe transporter, ferroportin-1 [47] (Fig. 1). Ferroportin-1 has been suggested to be down-regulated by the direct binding of the iron-regulatory hormone, hepcidin [48] (see below). This physical interaction then results in the internalization and degradation of ferroportin-1, leading to decreased cellular Fe efflux [48]. However, the mechanism of Fe release does not only appear to be dependent upon these molecules. Indeed, it is likely that the serum ferroxidase ceruloplasmin also plays a role in Fe efflux [11,49]. Iron released from the enterocyte via ferroportin-1 is subsequently bound to the serum Fe-binding and transport protein, transferrin (Tf) (Fig. 1).

The absorption of Fe from the gut is under the control of a number of molecules, including DMT1 [39,40], hepcidin [50], hemojuvelin [51] and the hemochromatosis gene product

(HFE) [52]. The expression of DMT1 at the apical surface of the enterocyte is controlled by the presence of an iron-responsive element (IRE) in the 3'-untranslated region (UTR) of its mRNA that is bound by the two IRPs, namely IRP1 and IRP2 [11,53]. High levels of cellular Fe results in low IRP-RNA-binding activity that prevents binding of the IRPs to the IRE in the 3'-UTR of DMT1 [53,54], leading to decreased stability of the mRNA and a subsequent decrease in its translation. The opposite response occurs during the period when Fe levels are low, leading to high DMT1 expression and increased dietary Fe uptake.

IRON TRANSPORT AND UPTAKE: TRANSFERRIN AND THE TRANSFERRIN RECEPTOR 1

Transferrin (Tf) is a plasma protein which binds two Fe3+ atoms with high affinity (for reviews see [11,55]). Diferric Tf can be bound by cells expressing the transferrin receptor 1 (TfR1) on the plasma membrane. The uptake of Fe from Tf is controlled by TfR1 expression which is modulated by intracellular Fe levels via IRP1 and IRP2 (for reviews see [11,55,56]). The interaction of Tf with the TfR1 is also regulated by the binding of the HFE protein [57].

Once Tf is bound to TfR1, the complex is internalized via receptor-mediated endocytosis [11,55]. An ATP-dependent proton pump in the endosomal membrane allows the release of Fe3+ from Tf by mediating a decrease in endosomal pH [11]. Once released, ferric iron is probably reduced to the ferrous state by an endosomal ferrireductase. A candidate for this molecule, namely the six-transmembrane epithelial antigen of the prostate 3 (Steap3), has recently been discovered [58]. Transfer of the so-formed Fe2+ through the endosomal membrane is mediated by DMT1 [39,40,54,59]. After the release of Fe from Tf, and its transport through the endosomal membrane, Fe2+ becomes part of the elusive intracellular Fe pool [60], where it can be incorporated into haem and non-haem Fe-containing proteins. Inside the cell, Fe2+ can be either stored in ferritin where it is converted into Fe3+, or used for metabolic functioning (e.g. haem synthesis; [11]). The nature of the labile intracellular pool (LIP) of Fe remains controversial. For instance, it may exist as compounds in the Fe2+ or Fe3+ state and the mechanism of how Fe is transported within cells remains a long unsolved question. Initially, Fe was suggested to be bound to low-molecular weight Fe complexes [60], while other studies have found no evidence of such intermediates [61,62]. Some evidence for the trafficking of Fe has been presented via organelle interactions and chaperone proteins [63]. After Fe delivery, the Tf-TfR1 complex returns to the plasma membrane via exocytosis and Tf is then released to the circulation for re-utilization [11].

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Responses

  • ruta
    Why fe2 does'nt get converted intoFe3?
    4 years ago

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