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Iron Metabolism and Iron Disorders Revisited in the Hepcidin

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Iron Metabolism and Iron Disorders Revisited in the Hepcidin CENTENARY REVIEW ARTICLE Iron metabolism and iron disorders revisited Ferrata Storti Foundation in the hepcidin era Clara Camaschella,1 Antonella Nai1,2 and Laura Silvestri1,2 1Regulation of Iron Metabolism Unit, Division of Genetics and Cell Biology, San Raffaele Scientific Institute, Milan and 2Vita Salute San Raffaele University, Milan, Italy ABSTRACT Haematologica 2020 Volume 105(2):260-272 ron is biologically essential, but also potentially toxic; as such it is tightly controlled at cell and systemic levels to prevent both deficien- Icy and overload. Iron regulatory proteins post-transcriptionally con- trol genes encoding proteins that modulate iron uptake, recycling and storage and are themselves regulated by iron. The master regulator of systemic iron homeostasis is the liver peptide hepcidin, which controls serum iron through degradation of ferroportin in iron-absorptive entero- cytes and iron-recycling macrophages. This review emphasizes the most recent findings in iron biology, deregulation of the hepcidin-ferroportin axis in iron disorders and how research results have an impact on clinical disorders. Insufficient hepcidin production is central to iron overload while hepcidin excess leads to iron restriction. Mutations of hemochro- matosis genes result in iron excess by downregulating the liver BMP- SMAD signaling pathway or by causing hepcidin-resistance. In iron- loading anemias, such as β-thalassemia, enhanced albeit ineffective ery- thropoiesis releases erythroferrone, which sequesters BMP receptor lig- ands, thereby inhibiting hepcidin. In iron-refractory, iron-deficiency ane- mia mutations of the hepcidin inhibitor TMPRSS6 upregulate the BMP- Correspondence: SMAD pathway. Interleukin-6 in acute and chronic inflammation increases hepcidin levels, causing iron-restricted erythropoiesis and ane- CLARA CAMASCHELLA [email protected] mia of inflammation in the presence of iron-replete macrophages. Our improved understanding of iron homeostasis and its regulation is having an impact on the established schedules of oral iron treatment and the Received: November 4, 2019. choice of oral versus intravenous iron in the management of iron deficien- Accepted: December 18, 2019. cy. Moreover it is leading to the development of targeted therapies for Pre-published: January 16, 2020. iron overload and inflammation, mainly centered on the manipulation of the hepcidin-ferroportin axis. doi:10.3324/haematol.2019.232124 Introduction Check the online version for the most updated information on this article, online supplements, Research advances in understanding the biological functions and homeostasis of and information on authorship & disclosures: iron have clarified its role in physiology and disease. Iron, essential for hemoglobin www.haematologica.org/content/105/2/260 synthesis, is indispensable to all cells for the production of heme and iron-sulfur (Fe/S) clusters, which are components of proteins/enzymes involved in vital biolog- ical processes such as respiration, nucleic acid replication and repair, metabolic ©2020 Ferrata Storti Foundation reactions and host defense. While essential for life, excess iron is toxic. The ability Material published in Haematologica is covered by copyright. to accept/release electrons explains the propensity of iron to damage cell compo- All rights are reserved to the Ferrata Storti Foundation. Use of nents and is the reason why body iron must be tightly regulated. The two-faced published material is allowed under the following terms and conditions: nature of iron is also evident in its disorders, which span from iron excess to iron https://creativecommons.org/licenses/by-nc/4.0/legalcode. deficiency and maldistribution, when some tissues are iron-loaded and others are Copies of published material are allowed for personal or inter- iron-deficient. nal use. Sharing published material for non-commercial pur- In the new millennium studies of genetic and acquired iron disorders and the poses is subject to the following conditions: https://creativecommons.org/licenses/by-nc/4.0/legalcode, development of their corresponding murine models have identified novel iron sect. 3. Reproducing and sharing published material for com- genes, proteins and pathways and unveiled the central role of the hepcidin-ferro- mercial purposes is not allowed without permission in writing portin axis in systemic iron homeostasis. This review summarizes recent advances from the publisher. in the understanding of iron trafficking, utilization and regulation, emphasizing the implications for iron disorders of hematologic interest; for further insights readers are directed to specific reviews.1-3 260 haematologica | 2020; 105(2) Hepcidin and iron disorders Iron trafficking to avoid toxicity. Although all cells may import, export or store iron, some have specific functions:1 e.g., erythroblasts Iron trafficking is an example of circular economy. Only are specialized in iron uptake, macrophages and entero- 1-2 mg iron are absorbed daily in the gut, compensating for cytes in iron export, and hepatocytes in iron storage. Within an equal loss; most iron (20-25 mg/daily) is recycled by cells most iron is transferred to mitochondria for heme and macrophages upon phagocytosis of erythrocytes. The site Fe/S cluster production. Heme is indispensable for hemo- of regulated non-heme iron uptake is the duodenum: non- globin, cytochromes and enzyme activity. Biogenesis of heme iron is imported from the lumen by the apical diva- Fe/S clusters is a process conserved from yeast to humans: lent metal transporter 1 (DMT1) after reduction from ferric this prosthetic group is essential to proteins involved in to ferrous iron by duodenal cytochrome B reductase genome maintenance, energy conversion, iron regulation (DCYTB). Absorption of heme exceeds that of non-heme and protein translation.14,15 In erythroblasts >80% iron is iron, though the mechanisms remain obscure. In entero- directed to mitochondria through a “kiss and run” mecha- cytes non-utilized iron is stored in ferritin - and lost with nism between endosomes and mitochondria.16 Mitoferrin 1 mucosal shedding - or exported to plasma by basolateral and 2 are iron transporters of the inner mitochondrial mem- membrane ferroportin according to the body’s needs brane, the former being essential for zebrafish and murine (Figure 1). erythropoiesis.17 Ferritin may store up to 4,500 iron atoms in a shell-like The role of transferrin and its receptors structure formed by 24 chains, comprising both heavy (H) The plasma iron pool is only 3-4 mg and must turn over chains, with ferroxidase activity, and light (L) chains.18 several times daily to meet the high (20-25 mg) demand of Ferritin storage of iron provides protection from oxidative erythropoiesis and other tissues. The iron carrier transferrin damage, and also saves an essential element for future is central to iron trafficking. Binding to its ubiquitous recep- needs. H-ferritin deletion is incompatible with life and its tor TFR1, transferrin delivers iron to cells through the well- conditional deletion in the gut deregulates the fine mecha- known endosomal cycle.1 This function is crucial not only nism of iron absorption causing iron overload.19 L-ferritin for erythropoiesis, but also for muscle4 and for B- and T- heterozygous mutations are rare and limited to the 5’ iron lymphocytes, as highlighted by a TFR1 homozygous muta- regulatory element (IRE) - leading to escape from iron regu- tion that causes combined immunodeficiency with only latory protein (IRP) control and constitutive high ferritin mild anemia.5 TFR1 is also essential in the gut to maintain synthesis in hyperferritinemia-cataract syndrome.20 Rare epithelial homeostasis independently of its function of an dominant mutations lead to elongated proteins and neuro- iron importer;6 in hepatocytes TFR1 is dispensable for basal ferritinopathies, a type of neurodegeneration caused by iron uptake, but essential in iron loading to finely tune the abnormal ferritin aggregates in the basal ganglia and other hepcidin increase.7 areas of the brain21 (Table 1). Transferrin is emerging as a key regulator of iron home- In the clinical setting serum ferritin is a marker of iron ostasis through binding to its second receptor TFR2, which deficiency when its level is low, and of iron has a lower binding affinity than TFR18 and whose expres- overload/inflammation when its level is increased, reflect- sion is restricted to hepatocytes and erythroblasts. When ing macrophage ferritin content. However, both the origin plasma iron concentration is high, diferric transferrin binds and the function of serum ferritin remain largely unex- TFR2 inducing upregulation of hepcidin in hepatocytes and plored. One hypothesis is that the secreted ferritin22 may be a reduction of erythropoietin responsiveness in erythroid re-uptaken by cells as an alternative mechanism of iron cells9 where TFR2 binds erythropoietin receptors.10 The recycling, e.g., when iron release from macrophages is lim- reverse occurs in iron deficiency. The dual function of trans- ited in inflammation. ferrin as an iron cargo and regulator seems to be dependent The cytosolic chaperon Poly (rC) binding protein 1 on the unequal ability of iron binding of the N and C termi- (PCBP1) delivers iron to ferritin,23 and Pcbp1 null mice have nal lobes and operates through the differential interaction microcytic anemia.24 Ferritin turnover occurs through “fer- of monoferric transferrin with the two receptors.11 ritinophagy”, an autophagic process
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