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Hepcidin and iron disorders
Iron trafficking
Iron trafficking is an example of circular economy. Only 1-2 mg iron are absorbed daily in the gut, compensating for an equal loss; most iron (20-25 mg/daily) is recycled by macrophages upon phagocytosis of erythrocytes. The site of regulated non-heme iron uptake is the duodenum: non- heme iron is imported from the lumen by the apical diva- lent metal transporter 1 (DMT1) after reduction from ferric to ferrous iron by duodenal cytochrome B reductase (DCYTB). Absorption of heme exceeds that of non-heme iron, though the mechanisms remain obscure. In entero- cytes non-utilized iron is stored in ferritin - and lost with mucosal shedding - or exported to plasma by basolateral membrane ferroportin according to the body’s needs (Figure 1).
The role of transferrin and its receptors
The plasma iron pool is only 3-4 mg and must turn over several times daily to meet the high (20-25 mg) demand of erythropoiesis and other tissues. The iron carrier transferrin is central to iron trafficking. Binding to its ubiquitous recep- tor TFR1, transferrin delivers iron to cells through the well- known endosomal cycle.1 This function is crucial not only for erythropoiesis, but also for muscle4 and for B- and T- lymphocytes, as highlighted by a TFR1 homozygous muta- tion that causes combined immunodeficiency with only mild anemia.5 TFR1 is also essential in the gut to maintain epithelial homeostasis independently of its function of an iron importer;6 in hepatocytes TFR1 is dispensable for basal iron uptake, but essential in iron loading to finely tune the hepcidin increase.7
Transferrin is emerging as a key regulator of iron home- ostasis through binding to its second receptor TFR2, which has a lower binding affinity than TFR18 and whose expres- sion is restricted to hepatocytes and erythroblasts. When plasma iron concentration is high, diferric transferrin binds TFR2 inducing upregulation of hepcidin in hepatocytes and a reduction of erythropoietin responsiveness in erythroid cells9 where TFR2 binds erythropoietin receptors.10 The reverse occurs in iron deficiency. The dual function of trans- ferrin as an iron cargo and regulator seems to be dependent on the unequal ability of iron binding of the N and C termi- nal lobes and operates through the differential interaction of monoferric transferrin with the two receptors.11
Iron recycling
Macrophages phagocytize senescent and damaged ery- throcytes, recover iron from heme through heme oxyge- nase (HMOX) 1 and may utilize, conserve or recycle the metal. The relevance of their role is strengthened by the severity of conditions in which recycling is altered. HMOX1 mutations in children cause a rare, severe disor- der12 and reduced recycling in inflammation causes anemia. Macrophage ferroportin is crucial for iron balance. Its expression is upregulated by heme and downregulated by inflammatory cytokines contributing to iron sequestration and its translation is repressed by iron. The protein is ulti- mately controlled at the post-translational level by hep- cidin.13
Cell iron import
Intracellular iron is used for multiple functions; if not uti- lized it is stored in ferritin, or exported by ferroportin, in order to maintain the labile iron pool within narrow limits
to avoid toxicity. Although all cells may import, export or store iron, some have specific functions:1 e.g., erythroblasts are specialized in iron uptake, macrophages and entero- cytes in iron export, and hepatocytes in iron storage. Within cells most iron is transferred to mitochondria for heme and Fe/S cluster production. Heme is indispensable for hemo- globin, cytochromes and enzyme activity. Biogenesis of Fe/S clusters is a process conserved from yeast to humans: this prosthetic group is essential to proteins involved in genome maintenance, energy conversion, iron regulation and protein translation.14,15 In erythroblasts >80% iron is directed to mitochondria through a “kiss and run” mecha- nism between endosomes and mitochondria.16 Mitoferrin 1 and 2 are iron transporters of the inner mitochondrial mem- brane, the former being essential for zebrafish and murine erythropoiesis.17
Ferritin may store up to 4,500 iron atoms in a shell-like structure formed by 24 chains, comprising both heavy (H) chains, with ferroxidase activity, and light (L) chains.18 Ferritin storage of iron provides protection from oxidative damage, and also saves an essential element for future needs. H-ferritin deletion is incompatible with life and its conditional deletion in the gut deregulates the fine mecha- nism of iron absorption causing iron overload.19 L-ferritin heterozygous mutations are rare and limited to the 5’ iron regulatory element (IRE) - leading to escape from iron regu- latory protein (IRP) control and constitutive high ferritin synthesis in hyperferritinemia-cataract syndrome.20 Rare dominant mutations lead to elongated proteins and neuro- ferritinopathies, a type of neurodegeneration caused by abnormal ferritin aggregates in the basal ganglia and other areas of the brain21 (Table 1).
In the clinical setting serum ferritin is a marker of iron deficiency when its level is low, and of iron overload/inflammation when its level is increased, reflect- ing macrophage ferritin content. However, both the origin and the function of serum ferritin remain largely unex- plored. One hypothesis is that the secreted ferritin22 may be re-uptaken by cells as an alternative mechanism of iron recycling, e.g., when iron release from macrophages is lim- ited in inflammation.
The cytosolic chaperon Poly (rC) binding protein 1 (PCBP1) delivers iron to ferritin,23 and Pcbp1 null mice have microcytic anemia.24 Ferritin turnover occurs through “fer- ritinophagy”, an autophagic process orchestrated by nuclear receptor co-activator (NCOA)4, a cargo molecule that directs ferritin to lysosomal degradation, to recover iron when needed.25,26 PCBP1 also delivers iron to prolyl- hydroxylase (PHD2) the enzyme that induces degradation of hypoxia inducible factors (HIF), one of the several links between iron and the hypoxia pathways.27
Iron export
The ubiquitous iron exporter ferroportin cooperates with the oxidases ceruloplasmin or hephaestin, to release ferric iron to transferrin. Enterocytes, macrophages, hepatocytes and trophoblasts express high ferroportin levels for their specific functions in iron homeostasis. Blocking iron export may be dangerous in some cells. For example, conditional ferroportin deletion in murine cardiomyocytes leads to local iron overload and cardiac failure;28 furthermore, specif- ic deletion of ferroportin in erythroblasts and erythrocytes leads to hemolytic anemia, due to the toxicity of iron derived from hemoglobin oxidation in an environment (red blood cells) with limited antioxidant capacity.29,30
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