Each cell in the body regulates its iron uptake, content, and utilization. The transport protein transferrin functions as the physiologic carrier of iron in the plasma and extracellular fluid. Each cell captures its share of circulating transferrin-bound iron using transferrin receptor 1, a glycoprotein on cell membranes that binds the transferrin-iron complex. The transferrin receptor with its cargo is internalized in an endocytic vesicle, where iron is released, and then the complex of the receptor and iron-free (apo)transferrin returns to the cell membrane, liberating apotransferrin into the plasma. Within the cell, the iron released from the endosome is either used for the synthesis of iron-containing biomolecules or stored in cytosolic ferritin, a protein that holds iron in a nontoxic form ready for mobilization when needed. The main determinant of iron uptake by each cell is the number of transferrin receptors on the cell surface. Within each cell, the intracellular availability of iron homeostatically regulates its cellular uptake and storage through the iron-regulatory proteins 1 and 2 (IRP1 and IRP2) whose levels are negatively regulated by available intracellular iron (Fig. 1). When iron is available in the cytoplasm, IRP1 acquires an iron-sulfur cluster to become a cytoplasmic enzyme, aconitase, and loses its iron-regulatory function, while IRP2 is degraded by an iron-dependent process. When available iron is low, the IRP concentrations rise and IRPs bind to RNA stem−loop structures called iron-responsive elements (IREs). IREs within the 3′-untranslated region of a messenger (m) RNA (e.g., transferrin receptor 1 mRNA) bind IRPs that protect the bound mRNA from degradation, making more mRNA available for translation, thus increasing protein production. Under the same conditions, IRP binding to IREs located in the 5′-untranslated region of an mRNA (e.g., cytosolic ferritin mRNA) impedes protein translation. Accordingly, a decrease in intracellular iron availability enhances transferrin receptor 1 protein synthesis, increasing iron import, and reduces cytosolic ferritin and iron storage. Conversely, an increase in intracellular iron avail ability reduces transferrin receptor 1 protein synthesis, inhibiting iron import, and augments cytosolic ferritin protein production and iron storage. In iron-replete cells with sufficient oxygen, F box and leucine-rich repeat protein 5 (FBXL5), a subunit of a ubiquitin ligase complex, monitors cytosolic iron and initiates iron-dependent degradation of iron-regulatory protein 2. Another system that contributes to cellular iron homeostasis is the regulated release of ferritin iron stores via a process called ferritinophagy. Here, a cargo carrier protein NCOA4 (nuclear receptor coactivator 4) delivers ferritin to the lysosomal compartment for the breakdown and release of its iron content. When cellular iron levels are high, NCOA4 itself is targeted for iron-dependent degradation via the ubiquitin proteasome system, so that NCOA4 concentrations in the cytoplasm are low, decreasing ferritinophagy and increasing ferritin iron storage. Conversely, under low cellular iron conditions, NCOA4 is increased, enhancing ferritinophagy and releasing more iron from ferritin to restore cellular iron levels.

Fig1. REGULATION OF CELLULAR IRON HOMEOSTASIS BY THE IRON-REGULATORY PROTEINS (IRP1 AND IRP2). The iron-regulatory proteins bind to RNA stem–loop structures called iron-responsive elements (IREs) when iron is absent and dissociate when iron is present. Binding IREs within the 3′-untranslated region of mRNA (e.g., transferrin receptor 1 [TfR1]) and some intestinal divalent metal transporter 1 (DMT1) isoforms increases mRNA stability, increasing protein synthesis. In contrast, binding IREs in the 5′-untranslated region of mRNA (e.g., cytosolic ferritin, ferroportin 1, erythroid aminolevulinic acid synthase [eALAS], mitochondrial aconitase [m-Aconitase], and hypoxia-inducible factor 2α [HIF-2α]) inhibits protein expression when iron is absent. In iron-replete cells, IRP1 assembles a cubane Fe/S cluster, acquiring aconitase activity while losing the ability to bind to IREs. In iron-replete cells, IRP2 interacts with F box and leucine-rich repeat protein 5 (FBXL5), a subunit of a ubiquitin ligase complex, leading to its ubiquitination and degradation by the proteasome. See text for details. (Reproduced with permission from Wallander ML, Leibold EA, Eisenstein RS. Molecular control of vertebrate iron homeostasis by iron-regulatory proteins. Biochim Biophys Acta.) 2006;1763:668.)

Altogether, regulation of intracellular iron homeostasis is mediated principally through iron-regulatory proteins 1 and 2 by their reciprocal control of the synthesis of transferrin receptor and ferritin and, in specialized cells, by controlling the synthesis of other essential proteins involved in iron homeostasis, including erythroid δ-aminolevulinic acid synthase 2 (eALAS), mitochondrial aconitase, hypoxia-inducible factor 2α (HIF-2α), intestinal divalent metal transporter 1 (DMT1) isoform I, and ferroportin. The NCOA4 system and other iron-dependent regulatory processes also contribute to cellular iron homeostasis.

Regulation of organismal iron content and tissue distribution is accomplished by the control of the entry of iron into plasma for transport by transferrin. Circulating iron is delivered to transferrin by specialized cells that can export iron, primarily splenic and hepatic macrophages that recycle iron from senescent RBCs (“iron-recycling macrophages”), hepatocytes that can mobilize iron from stores, and duodenal enterocytes that provide iron absorbed from the diet. To enter plasma, iron in these cells must pass through ferroportin (SLC40A1, a member of the solute carrier family of transporters), a 12-transmembrane-segment protein that is the sole known cellular iron exporter. Hepcidin, a small 25-amino acid peptide hormone secreted principally by hepatocytes, posttranslationally controls ferroportin iron transport and ferroportin membrane concentration. Hepcidin acts by binding to and occluding ferroportin and inducing its internalization, ubiquitination, and degradation, thereby inhibiting iron export from duodenal enterocytes, iron recycling macrophages, and iron-storing hepatocytes to plasma (Fig. 2). Hepatic hepcidin synthesis is stimulated by increases in body iron stores, plasma iron concentration, infection, and inflammation and is inhibited by hypoxemia and increased erythropoietic demand. The amount of iron in plasma in adults at any given time is only about 2 to 4 mg, while the daily amount of iron required for erythropoiesis is about 20 to 25 mg, so the iron in plasma turns over approximately every 2 to 4 hours. Increments in plasma hepcidin reduce the export capacity of ferroportin and the amount of ferroportin in cell membranes, thereby decreasing iron delivery to plasma. Continuing iron consumption for erythropoiesis and other processes then causes a prompt fall in plasma iron concentration as the small amounts of iron in plasma are rapidly depleted. Conversely, decrements in plasma hepcidin concentration increase the amount of ferroportin, producing a rise in plasma iron concentration.

Fig2. CONTROL OF IRON ENTRY INTO PLASMA BY FERROPORTIN AND HEPCIDIN IN THE REGULATION OF SYSTEMIC IRON HOMEOSTASIS. Ferroportin, a multitransmembrane-spanning protein that is the only known iron exporter in humans, is expressed at high concentrations on the basolateral membrane of duodenal enterocytes, reticuloendothelial macrophages, and hepatocytes (not shown). Plasma hepcidin binds to a site in the cavity of the “open out” conformation of ferroportin, occluding iron transport and inducing a conformational change that exposes a cytoplasmic loop for ubiquitination, leading to endocytosis and subsequent degradation of ferroportin in the lysosome. See text for details. DMT1, Divalent metal transporter 1; Hb, hemoglobin; RBC, red blood cells.

Less well understood is the role of microRNAs, short (approximately 22 nucleotides), noncoding RNAs that act as antisense regulators of target RNAs, providing a further degree of control of both cellular and systemic iron homeostasis.

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