Iron transport proteins: Gateways of cellular and systemic iron homeostasis

Abstract

Cellular iron homeostasis is maintained by iron and heme transport proteins that work in concert with ferrireductases, ferroxidases, and chaperones to direct the movement of iron into, within, and out of cells. Systemic iron homeostasis is regulated by the liver-derived peptide hormone, hepcidin. The interface between cellular and systemic iron homeostasis is readily observed in the highly dynamic iron handling of four main cell types: duodenal enterocytes, erythrocyte precursors, macrophages, and hepatocytes. This review provides an overview of how these cell types handle iron, highlighting how iron and heme transporters mediate the exchange and distribution of body iron in health and disease.

Keywords: bone marrow; heme; hepatocyte; iron; macrophage.

Figure 1.

Overview of the main organs and cell types involved in the regulation of systemic iron homeostasis. Enterocytes of the proximal small intestine absorb iron (as Fe²⁺, ●) into the circulation where it becomes bound (as Fe³⁺, ○) to its transport protein transferrin. Most circulating iron transferrin is taken up by erythrocyte precursors in the bone marrow, where the iron is incorporated into the heme component of hemoglobin in newly synthesized RBCs. Iron from senescent or damaged RBCs is recycled by macrophages of the liver, spleen, and bone marrow. Hepcidin, the iron-regulatory protein produced by hepatocytes, controls the flow of iron into the plasma by binding to ferroportin (on enterocytes, macrophages, and hepatocytes), causing its internalization and degradation. Hepcidin production is positively regulated by iron transferrin in the plasma, hepatic iron stores, and inflammation. Iron stores are sensed by hepatic sinusoidal endothelial cells, which produce BMP6, a key endogenous regulator of hepcidin expression. Hepcidin synthesis is negatively regulated by increased erythropoietic activity. BMP6, bone morphogenetic protein 6; DMT1, divalent metal-ion transporter-1; FPN, ferroportin; RBC, red blood cell; TF, transferrin.

Figure 2.

Cellular iron homeostasis. Four cell types are responsible for most of the routine iron handling in the body. A, enterocyte; B, erythrocyte precursor; C, macrophage; and D, hepatocyte. Depicted are the main pathways involved in the uptake, intracellular transport, storage, and efflux of non-heme iron and heme in these cells. ABCB10, ATP-binding cassette, subfamily B, member 10; CD163, cluster of differentiation 163; CP, ceruloplasmin; DMT1, divalent metal-ion transporter-1; FECH, ferrochelatase; FLVCR1 (feline leukemia virus subgroup C receptor 1); FPN, ferroportin; HMOX1, heme oxygenase 1; HP, hephaestin; HRG1, heme-responsive gene-1; LRP, low-density lipoprotein receptor-related protein; MFRN, mitoferrin 1; NRAMP1, natural resistance-associated macrophage protein 1; NHE3, Na⁺/H⁺ exchanger 3; RBC, red blood cell; STEAP3, six-transmembrane epithelial antigen of the prostate; TF, transferrin; TFR1, transferrin receptor 1; ZIP14, ZRT/IRT-like protein-14.