Overview of iron metabolism in health and disease

Abstract

Iron is an essential element for numerous fundamental biologic processes, but excess iron is toxic. Abnormalities in systemic iron balance are common in patients with chronic kidney disease and iron administration is a mainstay of anemia management in many patients. This review provides an overview of the essential role of iron in biology, the regulation of systemic and cellular iron homeostasis, how imbalances in iron homeostasis contribute to disease, and the implications for chronic kidney disease patients.

Keywords: Iron metabolism; anemia; chronic kidney disease; iron deficiency; iron overload.

Figure 1. Systemic iron homeostasis

Iron (Fe) circulates in the bloodstream bound to transferrin (TF). The majority of iron is delivered to the bone marrow for red blood cell (RBC) production, with lesser amounts going to other tissues for fundamental cellular processes and the excess transported to the liver for storage. Systemic iron homeostasis is maintained predominantly by recycling iron from RBCs via reticuloendothelial macrophages. A smaller amount of iron is provided by dietary absorption via duodenal enterocytes, which is matched by an unregulated loss of iron through desquamation and blood loss.

Figure 2. Cellular iron homeostasis

Depicted cell is an amalgam of many cell types; not all proteins/pathways are present in all cells. Iron enters into cells primarily by transferrin receptor 1 (TFR1)-mediated endocytosis. In endosomes, iron is freed from TF and reduced by a ferriductase (STEAP3) before exiting into the cytosol via divalent metal transporter (DMT1). TF and TFR1 are recycled back to the cell membrane for further cycles. DMT1 and other transporters (ZIP8, ZIP14) function in non-TF bound iron (NTBI) uptake pathways in some cell types. Other iron acquisition pathways in some cell types include uptake of hemoglobin(Hb)-haptoglobin, heme-hemopexin, heme, lipocalin 2, and ferritin via CD163, CD91, FLVCR2, SLC22A17, SCARA5, and TIM2 receptors respectively. In the cytosol, iron enters the labile iron pool (LIP), and is then utilized, stored, or exported out of the cell. Cytoplasmic iron transport is assisted in some cases by the chaperone poly (rC) binding protein 1 (PCBP1). Iron is mainly utilized by mitochondria for heme synthesis and iron-sulfur clusters (ISCs) biogenesis, with mitoferrins (MFRN1/2) playing a role in mitochondrial iron import and FLVCR1B playing a role in mitochondrial heme export. Excess iron in the cytosol is stored safely in ferritin. A mitochondrial form of ferritin (MTFT) is also expressed in some cell types. When the demand arises, ferritin can be targeted for autophagic turnover by nuclear receptor coactivator 4 (NCOA4) to release iron into the cytosolic LIP. Iron is exported out of the cell by ferroportin (FPN), assisted by ferroxidases ceruloplasmin (CP)/hephaestin (HP), followed by iron loading onto TF. FLVCR1A may play a role in heme export in some cell types.

Figure 3. Regulation of cellular iron homeostasis. A

Under iron-deficient conditions, iron regulatory proteins (IRPs) bind to iron-responsive elements (IREs) in the 5′ untranslated regions (UTR) of iron homeostasis mRNAs such as ferritin (FTH1, FTL1) and ferroportin (FPN) to block their translation, while IRP binding in the 3′ UTR of TFR1 and DMT1 enhances mRNA stability. This leads to an increase in iron uptake and a decrease in iron storage and export. Under the iron-replete conditions, the IRP-IRE interaction is inhibited: IRP2 is targeted for proteasomal degradation by F-box/leucine-rich repeat protein 5 (FBXL5), and IRP1 gets converted into cytosolic aconitase. B. Under low iron and oxygen (O₂) conditions, the regulatory hypoxia-inducible factor alpha subunit (HIFα) forms a complex with the ubiquitously expressed β subunit and translocates to the nucleus to regulate transcription of numerous iron homeostasis genes including TFR1, DMT1, FPN, CP, and erythropoietin (EPO). On the contrary, under iron-replete, normoxic conditions, HIFα subunits are targeted for proteasomal degradation by the oxygen- and iron-dependent prolyl hydroxylases (PHDs) and von Hippel-Lindau (VHL) protein. Abbreviations: ALAS, 5′-Aminolevulinate Synthase 2; Asc, ascorbate; UQ, ubiquitin; HRE, hypoxia response element; HO-1, heme oxygenase 1.

Figure 4. Regulation of systemic iron homeostasis

Secreted by the liver, hepcidin is a key iron hormone controls iron entry into circulation from absorptive enterocytes and iron-recycling macrophages by inducing FPN degradation. Iron loading and inflammation stimulate hepcidin transcription to prevent iron overload and sequester iron from pathogenic microorganisms (left panel). Iron deficiency and erythropoietic drive inhibit hepcidin transcription to provide adequate iron for erythropoiesis and other body requirements (right panel). Mediators of hepcidin regulation by iron, inflammation, and erythropoietic drive are indicated. Abbreviations: BMP, bone morphogenetic protein; HFE, hemochromatosis protein; TFR2, transferrin receptor 2; HJV, hemojuvelin; TMPRSS6 transmembrane protease serine 6; IL-6, interleukin 6; JAK, janus kinase; STAT3, signal transducer and activator of transcription 3; ERFE, erythroferrone.