Iron homeostasis signaling pathway


Pathway Description

Iron is essential for normal cell metabolism and plays an important role in processes including DNA synthesis, cellular respiration and oxygen transport. Iron can also generate toxic reactive oxygen species via the Fenton reaction, which can damage the cell. Loss of iron can happen via blood loss and via desquamation of intestinal epithelial cells, which contain ferritin. The greatest need for iron mobilization in the body is erythropoiesis.

In humans the excess cellular iron (hemochromatosis) can lead to cirrhosis, cardiomyopathy and diabetes mellitus. Excess iron content in the brain is associated with several inherited neurodegenerative diseases, including neurodegeneration, Friedreich's ataxia, Parkinson's, and Alzheimer's diseases.

Maintenance of cellular iron homeostasis is accomplished by the coordinated regulation of iron uptake, storage and export. Cytosolic iron is used for the formation of iron-containing proteins and for biosynthesis of Fe-S clusters and heme. Normal absorption of dietary iron begins in the duodenum, in the apical membrane of the enterocytes, where it enters in the form of inorganic iron via SLC11A2 or in the form of heme. Iron can either be stored in these cells in the form of ferritin or exit the cell and enter into circulation by the iron exporter SLC40A1. Ferritin is an intracellular iron storage protein complex consisting of heavy and light chain subunits that form a hollow sphere accepting up to 4,500 cations of Fe(III). Iron circulates in plasma bound to the glycoprotein transferrin (Tf), which has two high-affinity binding sites for Fe(III). Tf-Fe(III) binds to cell surface TFRC followed by internalization by clathrin-mediated endocytosis. Most circulating iron comes from the recycling of heme from senescent erythrocytes by reticuloendothelial macrophages. Hepatocytes play a dual role in systemic iron metabolism: they are the major site of iron storage and they secrete the master iron regulatory hormone hepcidin (HAMP), whose concentration increases in high iron or inflammatory conditions. Circulating HAMP binds to SLC40A1 and triggers its internalization and degradation, thus inhibiting the release of iron from enterocytes, hepatocytes, and macrophages.

ACO1 and IREB2 are the principal regulators, or iron-responsive proteins, of cellular iron homeostasis in vertebrates. IRPs are cytosolic proteins that bind to iron-responsive elements (IREs) in the 5' or 3' untranslated regions of mRNAs encoding proteins involved in iron uptake (TFRC, SLC11A2), sequestration (ferritin) and export (SLC40A1). Binding to the 5' UTR represses translation, while binding to the 3' UTR inhibits mRNA degradation. Both IRP proteins display IRE-binding under conditions of iron deprivation, but become post-translationally inactivated (ACO1) or degraded (IREB2) when the iron supply to cells is increased.

The IRE/IRP system provides key homeostatic regulation on the cellular level, whereas HAMP provides organism-wide homeostatic regulation, especially against iron overload.