Cells and proteins involved in iron homeostasis and heme synthesis. (A) The enterocyte: iron enters the body through the diet. Most iron absorption takes place in the duodenum and proximal jejunum. The absorption of iron takes place in different phases. In the luminal phase, iron is solubilized and converted from trivalent iron into bivalent iron by duodenal cytochrome B (DcytB). Heme is released by enzymatic digestion of hemoglobin and myoglobin during the mucosal phase, iron is bound to the brush border and transported into the mucosal cell by the iron transporter divalent metal transporter 1 (DMT1). Heme enters the enterocyte presumably through the heme carrier protein (HCP). In the cellular phase, heme is degraded by heme oxygenase and iron is released. Iron is either stored in cellular ferritin or transported directly to a location opposite the mucosal side. In the last phase of iron absorption, Fe²⁺ is released into the portal circulation by the basolateral cellular exporter ferroportin. Enterocytic iron export requires hephaestin, a multicopper oxidase homologous to ceruloplasmin (CP), which oxidizes Fe²⁺ to Fe³⁺ for loading onto transferrin. This cellular efflux of iron is inhibited by the peptide hormone hepcidin binding to ferroportin and subsequent degradation of the ferroportin-hepcidin complex. (B) The hepatocyte serves as the main storage for the iron surplus (most body iron is present in erythrocytes and macrophages). Furthermore, this cell, as the main producer of hepcidin, largely controls systemic iron regulation. The signal transduction pathway runs from the membrane to the nucleus, where bone morphogenetic protein (BMP) receptor, the membrane protein hemojuvelin (HJV), the hemochromatosis (HFE) protein, transferrin receptors 1 and 2, and matriptase-2 play an essential role. Through intracellular pathways, a signal is given to hepcidin transcription. The membrane-associated protease matriptase-2 (encoded by TMPRSS6) detects iron deficiency and blocks hepcidin transcription by cleaving HJV. (C) The macrophage belongs to the group of reticuloendothelial cells and breaks down senescent red blood cells. During this process, iron is released from heme proteins. This iron can either be stored in the macrophage as hemosiderin or ferritin or it may be delivered to the erythroid progenitor as an ingredient for new erythrocytes. The iron exporter ferroportin is responsible for the efflux of Fe²⁺ into the circulation. In both hepatocytes and macrophages, this transport requires the multicopper oxidase CP, which oxidases Fe²⁺ to Fe³⁺ for loading onto transferrin. (D) The erythroid progenitor: transferrin saturated with 2 iron molecules is endocytosed via the transferrin receptor 1. After endocytosis, the iron is released from transferrin, converted from Fe³⁺ to Fe²⁺ by the ferroreductase STEAP3, and transported to the cytosol by DMT1, where it is available mainly for the heme synthesis. Erythropoiesis has been reported to communicate with the hepatocyte by the proteins TWSG1, GDF15, and erythroferrone (Erfe) that inhibit signaling to hepcidin.^7,14,30  (E) The mitochondria of the erythroid progenitor: in the mitochondria the heme synthesis and Fe-S cluster synthesis takes place. In the first rate-limiting step of heme synthesis, 5-aminolevulinic acid (ALA) is synthesized from glycine and succinyl-coenzyme A by the enzyme δ-ALA synthase 2 (ALAS2) in the mitochondrial matrix. The protein SLC25A38 is located in the mitochondrial membrane and is probably responsible for the import of glycine into the mitochondria and might also export ALA to the cytosol. In the heme synthesis pathway, the uroporphyrinogen III synthase (UROS) in the cytosol is the fourth enzyme. It is responsible for the conversion of hydroxymethylbilane (HMB) to uroporphyrinogen III, a physiologic precursor of heme. In the last step, ferrochelatase (FECH), located in the mitochondrial intermembrane space, is responsible for the incorporation of Fe²⁺ into PPIX to form heme. GATA1 is critical for normal erythropoiesis, globin gene expression, and megakaryocyte development; it also regulates expression of UROS and ALAS2 in erythroblasts. The enzyme glutaredoxin-5 (GLRX5) plays a role in the synthesis of the Fe-S clusters, which are transported to the cytoplasm, probably via the transporter ABCB7. Figure adapted from van Rooijen et al.²  Professional illustration created by Debra T. Dartez.