From the Guidelines
Iron is transported from serum into the interstitial space primarily through transferrin, a glycoprotein that binds iron tightly in the bloodstream, and several cofactors are essential for its proper functioning, including a slightly acidic pH environment, bicarbonate ions, and the transferrin receptor (TfR1) on cell surfaces.
Mechanism of Iron Transport
The process of iron transport from serum into the interstitial space involves the binding of iron to transferrin, which then interacts with the transferrin receptor on the surface of cells, leading to the internalization of the transferrin-receptor complex through endocytosis 1.
Cofactors Required for Transferrin Function
For transferrin to function effectively, several cofactors are necessary, including:
- A slightly acidic pH environment (around 5.5) at the cell surface to release its iron cargo
- Bicarbonate ions, which serve as synergistic anions that stabilize iron binding to transferrin in serum and facilitate its release at the cell membrane
- The transferrin receptor (TfR1) on cell surfaces, necessary for recognizing and binding transferrin-iron complexes
- Copper, needed for ceruloplasmin (a ferroxidase) to convert ferrous iron (Fe²⁺) to ferric iron (Fe³⁺), the form that binds to transferrin
Cellular Internalization of Iron
For cells to internalize iron, they require:
- Functional endocytosis machinery to internalize the transferrin-receptor complex
- ATP to power this process
- STEAP proteins (metalloreductases) to reduce iron back to Fe²⁺ inside endosomes for transport across the endosomal membrane via DMT1 (divalent metal transporter 1)
- Vitamin C, which enhances cellular iron uptake by maintaining iron in its reduced state, as noted in the context of iron metabolism and transport 1.
Clinical Implications
Understanding the complex process of iron transport and the cofactors required for transferrin function is crucial for managing iron deficiency and related disorders, particularly in patients with chronic kidney disease, where iron deficiency is a common complication 1.
From the Research
Mechanism of Iron Transport
- Iron is transported from serum into the interstitial space through the binding of iron-laden transferrin to the cell-surface transferrin receptor 1, resulting in endocytosis and uptake of the metal cargo 2.
- The transferrin receptor plays a crucial role in mediating cellular uptake of iron from transferrin, involving the binding of transferrin to the receptor, internalization of transferrin within an endocytic vesicle, and release of iron from the protein by a decrease in endosomal pH 3.
Cofactors Required for Transferrin Function
- Transferrin requires the transferrin receptor to function properly, as the receptor mediates the cellular uptake of iron from transferrin 4, 3.
- Ceruloplasmin or hephestin are required for the ferroxidase activity that loads iron safely onto transferrin, allowing iron to be released from cells by the iron export protein ferroportin1 5.
Cellular Internalization of Iron
- Internalized iron is transported to mitochondria for the synthesis of haem or iron-sulfur clusters, which are integral parts of several metalloproteins, and excess iron is stored and detoxified in cytosolic ferritin 2.
- The regulation of iron metabolism is controlled at different levels and by diverse mechanisms, including the IRE (iron-responsive element)/IRP (iron-regulatory protein) system, which maintains iron homoeostasis in various cell types and contributes to systemic iron balance 2, 3.