Iron is a micronutrient required for almost all life forms. As an active metal, it is involved in fundamental biological processes, primarily serving as a component of proteins responsible for oxygen transport and cellular energy generation. Because free iron is highly reactive and toxic, the body has evolved a complex system to manage its lifecycle. This system ensures iron is acquired, delivered to tissues, safely stored, and efficiently recycled.
Dietary Intake and Intestinal Absorption
Iron enters the body through the diet in two primary forms: heme iron and non-heme iron. Heme iron, sourced from animal proteins, is the most easily absorbed form. Non-heme iron, found in plant-based foods, is more challenging for the body to acquire.
The primary site for iron uptake is the duodenum, the first section of the small intestine. Non-heme iron (ferric state) must first be converted to the ferrous state to be absorbed. This reduction is facilitated by ferrireductases on the intestinal cell surface, a process aided by stomach acid. The resulting ferrous iron is then transported into the enterocyte through Divalent Metal Transporter 1 (DMT1).
Heme iron follows a more efficient route, entering the enterocyte directly. Once inside, an enzyme breaks down the heme molecule, releasing the iron into the cell’s internal pool. Iron not immediately needed is prepared for export into the bloodstream via the sole cellular iron exporter, Ferroportin (FPN1). As iron passes through Ferroportin, it is immediately oxidized back to the ferric state by Hephaestin, readying it to bind to its transport protein in the circulation.
Transport Through the Bloodstream and Active Utilization
Once iron enters the plasma, it is immediately bound by the glycoprotein Transferrin (Tf), which is synthesized primarily by the liver. Transferrin safely carries the toxic ferric iron through the bloodstream, preventing it from generating harmful free radicals and ensuring targeted delivery to cells.
Tissues acquire iron from Transferrin via specific receptors, primarily Transferrin Receptor 1 (TfR1). Cells with high iron demand, such as erythroid precursor cells in the bone marrow, express many of these receptors. The iron-Transferrin complex binds to TfR1 and is internalized through receptor-mediated endocytosis.
Inside the cell, the complex enters an endosome where acidification causes the iron to detach from Transferrin. The freed iron is then transported into the cytoplasm. The majority of this acquired iron is directed toward the mitochondria for incorporation into the Heme component of hemoglobin. Hemoglobin synthesis in the bone marrow consumes the largest share of daily iron, forming the oxygen-carrying molecules in red blood cells.
Cellular Storage and Recycling Mechanisms
The body manages iron reserves by storing excess iron in a safe, non-toxic form within specialized proteins. The main storage molecule is Ferritin, a spherical protein complex that can sequester thousands of iron atoms. Ferritin is found in virtually all cells, with the largest reserves held in the liver, spleen, and bone marrow.
When iron levels are very high, Ferritin can aggregate into Hemosiderin, a less soluble, long-term storage complex often found within macrophages. Hemosiderin is a reserve form of iron that is less readily available than Ferritin.
The most substantial source of daily iron comes from the recycling of aged red blood cells. Red blood cells circulate for about 120 days before being engulfed by specialized macrophages, primarily in the spleen and liver. These macrophages break down hemoglobin, liberating the iron. This recycled iron is either stored as Ferritin or released back into the circulation via Ferroportin, supplying about 90% of the body’s daily iron needs.
Systemic Regulation of Iron Homeostasis
Since the body lacks a mechanism for actively excreting excess iron, regulation focuses entirely on controlling its absorption and release. The master regulator of systemic iron homeostasis is the peptide hormone Hepcidin, produced predominantly by the liver. Hepcidin acts as a negative feedback signal, linking the body’s iron stores to the amount of iron absorbed from the gut.
When iron stores are high, the liver increases Hepcidin secretion into the bloodstream. Hepcidin binds to the iron export channel Ferroportin on the surface of iron-exporting cells, including intestinal enterocytes and recycling macrophages.
The binding of Hepcidin causes Ferroportin to be internalized and degraded within the cell. By destroying the export channel, Hepcidin traps iron within storage cells, reducing the amount entering the plasma and preventing overload. Conversely, low iron levels decrease Hepcidin production, allowing Ferroportin to remain active and maximize iron absorption and release.