Mention the different steps in the metabolism of iron. What are the functions that require iron? Add a note on the regulatory mechanisms that ensure stable titers of iron in the body.

Iron Metabolism: A Step-by-Step Breakdown

Iron metabolism can be broadly divided into several key steps:

1. Dietary Iron Absorption

• Heme Iron: Absorbed intact by enterocytes via Heme Carrier Protein 1 (HCP1).
• Non-Heme Iron (Fe³⁺): Reduced to Fe²⁺ by Duodenal Cytochrome b reductase (Dcytb). Fe²⁺ is then transported into the enterocyte by Divalent Metal Transporter 1 (DMT1).
• Export from Enterocyte: Fe²⁺ is either stored as ferritin within the enterocyte or transported into the circulation via Ferroportin (FPN). Hepcidin regulates FPN activity.

2. Iron Transport in Circulation

Once exported from the enterocyte, Fe²⁺ is oxidized to Fe³⁺ by hephaestin (a copper-containing ferroxidase). Fe³⁺ is then bound to transferrin, the primary iron transport protein in the plasma.

3. Iron Storage

Iron is stored primarily in the liver, spleen, and bone marrow as ferritin and hemosiderin.

• Ferritin: A soluble protein that stores iron in a non-toxic form.
• Hemosiderin: An insoluble form of iron storage, representing partially degraded ferritin.

4. Iron Utilization

Transferrin delivers Fe³⁺ to cells via transferrin receptors (TfR1 and TfR2). Once inside the cell, Fe³⁺ is reduced to Fe²⁺ and incorporated into various iron-containing proteins.

5. Iron Excretion

Iron excretion is limited. Minimal amounts are lost through:

• Shedding of epithelial cells (skin, gut).
• Menstrual blood loss.
• Minor amounts in bile and feces.

Functions Requiring Iron

Iron plays a critical role in numerous physiological functions:

• Oxygen Transport: Hemoglobin in red blood cells and myoglobin in muscle cells bind oxygen.
• Electron Transport Chain: Cytochromes in the electron transport chain are iron-containing proteins essential for ATP production.
• DNA Synthesis: Ribonucleotide reductase, an iron-dependent enzyme, is crucial for DNA synthesis.
• Immune Function: Iron is required for the proliferation and function of immune cells.
• Enzyme Cofactor: Iron serves as a cofactor for numerous enzymes involved in various metabolic pathways (e.g., catalase, peroxidase).

Regulatory Mechanisms Ensuring Stable Iron Titers

The body employs several mechanisms to maintain iron homeostasis:

1. Hepcidin Regulation

Hepcidin, a peptide hormone produced by the liver, is the central regulator of iron homeostasis. It binds to ferroportin, causing its internalization and degradation, thereby inhibiting iron export from enterocytes, macrophages, and hepatocytes.

• Increased Hepcidin: Induced by high iron levels, inflammation (via IL-6), and erythropoiesis suppression.
• Decreased Hepcidin: Induced by iron deficiency, hypoxia, and increased erythropoiesis.

2. Iron Regulatory Proteins (IRPs)

IRPs (IRP1 and IRP2) are cytoplasmic proteins that regulate the translation of mRNA encoding proteins involved in iron metabolism.

• Iron-deficient state: IRPs bind to Iron Responsive Elements (IREs) in mRNA, affecting translation. They repress the translation of ferritin mRNA (reducing iron storage) and stabilize the translation of TfR1 mRNA (increasing iron uptake).
• Iron-replete state: Iron binds to IRPs, reducing their affinity for IREs, leading to increased ferritin synthesis and decreased TfR1 synthesis.

3. Erythropoietic Regulation

Erythropoiesis (red blood cell production) increases iron demand. Erythroferrone, a hormone produced by erythroblasts, suppresses hepcidin expression, increasing iron availability for hemoglobin synthesis.