Iron Metabolism
Introduction
Iron metabolism refers to the set of chemical reactions that maintain human homeostasis of iron at both the systemic and cellular levels. Iron is an essential element for most living organisms, including humans, playing a crucial role in various physiological processes such as oxygen transport, DNA synthesis, and electron transport. This article delves into the intricate mechanisms of iron absorption, transport, storage, and regulation within the human body.
Iron Absorption
Iron absorption primarily occurs in the duodenum and upper jejunum of the small intestine. Dietary iron exists in two forms: heme iron, found in animal products, and non-heme iron, found in plant-based foods. Heme iron is absorbed more efficiently than non-heme iron.
Heme Iron Absorption
Heme iron is absorbed via a specialized transporter known as heme carrier protein 1 (HCP1). Once inside the enterocyte, heme oxygenase cleaves the heme molecule to release ferrous iron (Fe²⁺).
Non-Heme Iron Absorption
Non-heme iron absorption is a more complex process. Ferric iron (Fe³⁺) must first be reduced to ferrous iron (Fe²⁺) by the enzyme duodenal cytochrome B (Dcytb). Ferrous iron is then transported across the enterocyte membrane by divalent metal transporter 1 (DMT1).
Iron Transport
Once absorbed, iron is transported in the bloodstream bound to a glycoprotein called transferrin. Transferrin binds to iron with high affinity, ensuring its solubility and preventing free iron from catalyzing the formation of harmful free radicals.
Transferrin and Transferrin Receptors
Transferrin-bound iron is delivered to cells via transferrin receptors (TfR) on the cell surface. The transferrin-receptor complex undergoes endocytosis, and the acidic environment of the endosome facilitates the release of iron from transferrin. The iron is then transported out of the endosome by DMT1.
Iron Storage
Iron is stored in cells in the form of ferritin and hemosiderin. Ferritin is a globular protein complex that can store up to 4500 iron atoms in a soluble and non-toxic form. Hemosiderin is an insoluble form of storage iron, typically found within macrophages.
Ferritin
Ferritin is composed of 24 subunits forming a hollow shell, which allows iron to be stored in a mineralized form. It serves as a buffer against iron deficiency and overload.
Hemosiderin
Hemosiderin is formed when ferritin is degraded, usually in conditions of iron overload. It is less readily available for mobilization compared to ferritin.
Iron Regulation
Iron homeostasis is tightly regulated at both the systemic and cellular levels to prevent iron deficiency and toxicity. Key regulators include hepcidin, ferroportin, and iron regulatory proteins (IRPs).
Hepcidin
Hepcidin is a peptide hormone produced by the liver that plays a central role in iron regulation. It inhibits iron absorption by binding to and inducing the degradation of ferroportin, the only known iron exporter in cells.
Ferroportin
Ferroportin is a transmembrane protein that exports iron from cells into the bloodstream. It is highly expressed in enterocytes, macrophages, and hepatocytes.
Iron Regulatory Proteins
Iron regulatory proteins (IRPs) control the post-transcriptional regulation of genes involved in iron metabolism. They bind to iron-responsive elements (IREs) on mRNA, modulating the stability and translation of these mRNAs.
Iron Disorders
Disruptions in iron metabolism can lead to various disorders, including iron deficiency anemia, hemochromatosis, and anemia of chronic disease.
Iron Deficiency Anemia
Iron deficiency anemia is characterized by a decrease in hemoglobin levels due to insufficient iron. Symptoms include fatigue, pallor, and shortness of breath. It is commonly caused by inadequate dietary intake, increased iron requirements, or chronic blood loss.
Hemochromatosis
Hemochromatosis is a genetic disorder characterized by excessive iron absorption and accumulation in tissues, leading to organ damage. It is most commonly caused by mutations in the HFE gene.
Anemia of Chronic Disease
Anemia of chronic disease is associated with chronic infections, inflammatory diseases, and malignancies. It is characterized by impaired iron utilization and sequestration of iron within macrophages, mediated by increased hepcidin levels.