Upon entry into the plasma, iron attaches to transferrin, an abundant circulating protein that binds iron with extremely high affinity. Transferrin serves three important functions. Firstly, it keeps iron in solution. In an aqueous, neutral pH environment iron exists as Fe3+ ion, which is almost insoluble. Secondly, it renders iron non-reactive, and allows it to circulate in a safe, non-toxic form. Thirdly, transferrin facilitates the delivery of iron to cells bearing transferrin receptors on their surfaces.
Most differentiated cell types express few, if any, transfer-rin receptors, but there are three important exceptions: tumor cells, activated lymphocytes and erythroid precursors. Tumor cells presumably use transferrin receptors to optimize iron uptake to support rapid proliferation. The same may be true for activated lymphocytes. However, the greatest demand for iron is by erythroid precursors, to support the large-scale production of hemoglobin. In normal adults, about two-thirds of the total body iron endowment is found in hemoglobin, distributed among erythroid precursor cells and circulating erythrocytes.
Binding of iron-loaded transferrin to the transferrin receptor initiates receptor-mediated endocytosis, as shown in Figure 13.2. Portions of the cell membrane bearing liganded transferrin receptors invaginate into the cytoplasm, and bud off as intracellular vesicles (endosomes). Protons are pumped into the endosome to lower their internal pH, leading to the release of iron from transferrin. The liberated iron then leaves
QD Fe2transferrin TT -Apo-transferrin
QD Fe2transferrin TT -Apo-transferrin
The transferrin cycle of receptor-mediated endocytosis is initiated by binding of diferric (Fe2)- transferrin to a cell surface transferrin receptor. The ligand-receptor complex is internalized by invaginationof clatlorin-coated pits to form specialized endosomes. Influx of protons into the endosome decreases its pH to approximately 5.5, facilitating release of iron from transferrin. The iron is then transferred to the cytoplasm by DMT1. Apo-transferrin and transferrin receptor return to the cell surface for further cycles of iron uptake.
the endosome to enter the cytoplasm. This also requires a transmembrane transport step, which is probably mediated by DMT1 and facilitated by the low endosomal pH. Within the cytoplasm, iron is shuttled (by unknown mechanisms) to sites of use and storage. Meanwhile, transferrin and transfer-rin receptor proteins return to the cell surface, where they become available for further cycles of iron delivery.
Why should cells have evolved the complicated transfer-rin cycle when it is possible to take up iron directly? There are at least two likely answers. Firstly, tight binding of iron to transferrin is advantageous while iron is in the circulation, but it complicates the matter of bringing iron into cells. The pH-dependent release of iron, occurring in a controlled in-tracellular environment, solves the problem of liberating the iron. Secondly, binding of iron-loaded transferrin to trans-ferrin receptors serves to concentrate iron in the vicinity of DMT1, probably achieving much higher local iron concentrations than would be possible without such a mechanism. This allows more efficient iron uptake by cells with large needs (erythroid precursors, tumor cells, activated lymphocytes) without exposing other cells to unnecessary iron.
Undoubtedly, other cell types use these and other schemes for assimilating iron. Hepatocytes and macrophages are particularly important in iron homeostasis and their iron uptake mechanisms, though not well understood, deserve mention. Hepatocytes express transferrin receptors and likely take up iron through the transferrin cycle. Hepatocytes are also capable of taking up non-transferrin-bound iron when the plasma iron concentration exceeds the binding capacity of transfer-rin. This is an abnormal situation, because there are usually about three times as many transferrin iron-binding sites as are needed (i.e. transferrin is normally about 30% saturated with iron). But patients with iron overload may have more iron than transferrin can accommodate, and that excess iron appears to be rapidly removed from the circulation by hepatocytes. The molecular mechanism for hepatic non-transferrin-bound iron uptake has not yet been identified. Furthermore, it is not known how hepatocyte iron stores are later mobilized when the iron they contain is needed elsewhere.
As discussed earlier, reticuloendothelial macrophages obtain iron by phagocytosing and breaking down erythrocytes. This probably takes place in discrete phagocytic vesicles within the cells, and likely involves the action of heme oxygenase, an enzyme that catalyzes the degradation of heme. Similar to intestinal cells and hepatocytes, reticuloendothelial macrophages partition their iron content into retained and released portions. This process is probably regulated in response to the iron needs of the body. While there is currently no direct way to measure how much iron is retained and how much is released, commonly used laboratory tests provide some information. The concentration of serum iron (and hence the transferrin saturation) is determined by two factors: macrophage iron release and erythroid iron utilization. When erythropoiesis occurs at a steady rate, transferrin saturation is determined primarily by the rate of macrophage iron release, increasing when there is increased iron export and decreasing when iron is retained or when less iron is being recycled from erythro-cytes. In contrast, the concentration of serum ferritin roughly correlates with the amount of storage iron in the body. The origin(s) of serum ferritin is not known, but it appears to be derived primarily from hepatocytes and reticuloendothelial macrophages. Serum ferritin is not a very accurate indicator, however, because levels are increased by inflammation, tissue damage and rare congenital hyperferritinemia disorders. Nonetheless, a low serum ferritin value invariably indicates depleted iron stores.
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