International Journal of Molecular Sciences Review Hepcidin-Ferroportin Interaction Controls Systemic Iron Homeostasis Elizabeta Nemeth 1 and Tomas Ganz 2,* 1 Department of Medicine, University of California, Los Angeles, CA 90095, USA; [email protected] 2 Departments of Medicine and Pathology, University of California, Los Angeles, CA 90095, USA * Correspondence: [email protected] Abstract: Despite its abundance in the environment, iron is poorly bioavailable and subject to strict conservation and internal recycling by most organisms. In vertebrates, the stability of iron concentration in plasma and extracellular fluid, and the total body iron content are maintained by the interaction of the iron-regulatory peptide hormone hepcidin with its receptor and cellular iron exporter ferroportin (SLC40a1). Ferroportin exports iron from duodenal enterocytes that absorb dietary iron, from iron-recycling macrophages in the spleen and the liver, and from iron-storing hepatocytes. Hepcidin blocks iron export through ferroportin, causing hypoferremia. During iron deficiency or after hemorrhage, hepcidin decreases to allow iron delivery to plasma through ferroportin, thus promoting compensatory erythropoiesis. As a host defense mediator, hepcidin increases in response to infection and inflammation, blocking iron delivery through ferroportin to blood plasma, thus limiting iron availability to invading microbes. Genetic diseases that decrease hepcidin synthesis or disrupt hepcidin binding to ferroportin cause the iron overload disorder hereditary hemochromatosis. The opposite phenotype, iron restriction or iron deficiency, can result from genetic or inflammatory overproduction of hepcidin. Keywords: iron deficiency; iron overload; hemochromatosis; anemia; metal transport Citation: Nemeth, E.; Ganz, T. Hepcidin-Ferroportin Interaction Controls Systemic Iron Homeostasis. Int. J. Mol. Sci. 2021, 22, 6493. 1. The Roles of Iron https://doi.org/10.3390/ijms22126493 Iron is an essential trace element for nearly all living organisms. Even though iron is one of the most abundant elements in the Earth’s crust, ferric iron, an oxidized form Academic Editor: Wojciech Bal common in the oxygen-rich environment on the surface of the Earth, is poorly soluble and difficult to access by most life forms. Accordingly, biological organisms have evolved Received: 2 June 2021 mechanisms that conserve iron and recycle it internally. In adult humans, total body iron Accepted: 14 June 2021 Published: 17 June 2021 content is approximately 3–4 g, whereas normal daily losses are only 1–2 mg. To remain in iron balance, healthy humans must absorb a similar amount of iron from their diets. The ability of iron to donate or accept an electron in cellular and extracellular envi- Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in ronments is what makes it a versatile catalytic component of many enzymes involved in published maps and institutional affil- energy-producing bioreactions and critical biosynthetic pathways, as well as in enzymes iations. that generate reactive oxygen species for host defense. Iron also coordinates oxygen in hemoglobin and myoglobin, molecules involved in oxygen transport and its cellular storage. In biological systems, iron carries out its function in association with three common types of moieties: iron coordinated by protein side chains, iron complexed within the porphyrin ring of heme, and iron within iron-sulfur clusters. Outside of these controlled chemical Copyright: © 2021 by the authors. environments, iron displays promiscuous reactivity that can damage cells and tissues. Licensee MDPI, Basel, Switzerland. This article is an open access article 2. Iron Compartments and Flows distributed under the terms and conditions of the Creative Commons Biological organisms closely regulate intracellular and extracellular iron concentra- Attribution (CC BY) license (https:// tions, navigating between the twin threats of inadequate iron supply that would limit creativecommons.org/licenses/by/ critical functions, and uncontrolled iron excess that could be toxic to the organism. Sys- 4.0/). temic iron homeostasis, best understood in humans and laboratory rodents, is maintained Int. J. Mol. Sci. 2021, 22, 6493. https://doi.org/10.3390/ijms22126493 https://www.mdpi.com/journal/ijms Int. J. Mol. Sci. 2021, 22, x FOR PEER REVIEW 2 of 13 2. Iron Compartments and Flows Biological organisms closely regulate intracellular and extracellular iron concentra- tions, navigating between the twin threats of inadequate iron supply that would limit crit- ical functions, and uncontrolled iron excess that could be toxic to the organism. Systemic Int. J. Mol. Sci. 2021, 22, 6493 iron homeostasis, best understood in humans and laboratory rodents, is maintained2 ofby 13 regulating intestinal iron absorption, the concentration of iron in blood plasma and extra- cellular fluid, the distribution of iron among organs and tissues, and the amount of iron keptby regulating in stores. Iron intestinal dyshomeostasis iron absorption, can manifest the concentration as total body ofiron iron deficit in blood (iron plasmadeficiency) and orextracellular excess (iron fluid, overload), the distribution as well as iron of ironmaldistribution among organs among and tissues tissues, in and which the individ- amount ualof irontissues kept or inorgans stores. may Iron become dyshomeostasis iron-deficient can or manifest iron-overloaded. as total body Such iron iron deficit disorders (iron maydeficiency) be caused or excessby genetic (iron lesions overload), that directly as well impair as iron iron maldistribution regulation, or among conditions tissues that in impactwhich individualiron regulation tissues indirectly. or organs may become iron-deficient or iron-overloaded. Such ironAlthough disorders all may cells be in caused a multicellular by genetic organi lesionssm contain that directly iron, systemic impair iron iron regulation, homeostasis or isconditions primarily that affected impact by iron the regulationfollowing indirectly.compartments: the erythron (red blood cells and their precursorsAlthough all in cellserythropoietic in a multicellular organs), organism two types contain of stores iron, (hepatocytes systemic iron of the homeostasis liver and macrophagesis primarily affectedof the spleen by the and following the liver), compartments: blood plasma whic the erythronh moves iron (red between blood cells tissues and andtheir organs, precursors and absorptive in erythropoietic enterocytes organs), in the two duodenum types of storesthrough (hepatocytes which iron ofenters the liver the body,and macrophages ordinarily to ofreplace the spleen small and losses the from liver), the blood body plasma caused which by shedding moves ironof iron-con- between tainingtissues cells and (Figure organs, 1). and absorptive enterocytes in the duodenum through which iron enters the body, ordinarily to replace small losses from the body caused by shedding of iron-containing cells (Figure1). Figure 1. The key iron flows and compartments. Figure 1. The key iron flows and compartments. The largest of these iron compartments is the erythron (erythrocytes and their precur- sors),The which largest contains of these approximately iron compartments 2–3 g of is iron, the representingerythron (erythrocytes about 2/3–3/4 and oftheir the pre- total cursors),body iron which in adult contains humans. approximately Erythroid iron 2–3 is almostg of iron, entirely representing contained about within 2/3–3/4 hemoglobin, of the totalat the body concentration iron in adult of humans. 1 g of iron Erythroid per liter iron of is packed almost erythrocytes. entirely contained Thesecond within hemo- largest globin,compartment at the concentration are the hepatocyte of 1 g stores, of iron where per liter upto of 1 packed g of iron erythrocytes. is contained The in cytoplas- second largestmic ferritin compartment of hepatocytes. are theThe hepatocyte stores are stores, highly where variable up to and 1 cang of beiron nearly is contained depleted in in cytoplasmicmany women ferritin of reproductive of hepatocytes. age becauseThe stores of are menstrual highly variable blood loss and combined can be nearly with lowde- pleteddietary in intake. many Thewomen recycling of reproductive macrophages age in because the spleen, of menstrual liver and blood marrow loss function combined as a withrapid low turnover dietary compartment intake. The recycling [1]. The spleen,macrophages which in represents the spleen, a substantial liver and marrow portion func- of the tionmacrophage as a rapid storage turnover compartment, compartment normally [1]. The contains spleen, which only about represents 0.05 g ofa substantial iron but has por- the tioncapacity of the for macrophage much larger storage amounts compartment, [2]. Only about normally 0.3 g contains of iron are only contained about 0.05 in theg of other iron buttissues, has the in myoglobincapacity for of much muscles larger and amounts in iron-containing [2]. Only about enzymes. 0.3 g of iron are contained in theIron other is tissues, transported in myoglobin around the of body muscles on blood and in plasma iron-containing carrier protein enzymes. transferrin, whose two iron-binding sites are normally 20–45% occupied. Each cell in the body has transferrin receptors (TfR1) that are endocytosed into acidified endosomes where iron dissociates from the TfR1-transferrin complex and is transported across the endosomal membrane into the cytoplasm. The transferrin