From the Guidelines
Iron is transported from serum into the interstitial space primarily through the mechanism of ferroportin, which exports Fe2+ into the circulation, and then the multicopper oxidase ceruloplasmin (CP) oxidizes Fe2+ to Fe3+ for loading onto transferrin. This process is crucial for maintaining iron homeostasis in the body. According to the study published in Blood 1, ferroportin is responsible for the efflux of Fe2+ into the circulation in both hepatocytes and macrophages. The multicopper oxidase CP then oxidizes Fe2+ to Fe3+ for loading onto transferrin, which can then transport iron to other cells and tissues.
Key Steps in Iron Transport
- Iron is exported from cells into the circulation by ferroportin
- The multicopper oxidase CP oxidizes Fe2+ to Fe3+ for loading onto transferrin
- Transferrin binds to transferrin receptors on cell surfaces, triggering receptor-mediated endocytosis
- Iron is released from transferrin in the endosome and transported into the cytoplasm by DMT1
The study 1 highlights the importance of ferroportin and CP in iron transport, and how they work together to maintain iron homeostasis. This regulated process ensures that iron is properly distributed throughout the body, while preventing the accumulation of free iron, which can cause oxidative damage.
Regulation of Iron Transport
- Hepcidin binding to ferroportin inhibits iron export from cells
- The signal transduction pathway in hepatocytes controls systemic iron regulation
- Erythropoiesis communicates with hepatocytes through proteins such as TWSG1, GDF15, and erythroferrone (Erfe) to regulate iron transport.
From the FDA Drug Label
Following intravenous administration, Venofer is dissociated into iron and sucrose and the iron is transported as a complex with transferrin to target cells including erythroid precursor cells. The mechanism that transports iron from serum into the interstitial space is not explicitly stated in the drug label, but it can be inferred that transferrin plays a role in transporting iron to target cells.
- The drug label does not provide a direct answer to how iron is transported from serum into the interstitial space. However, based on the information provided, it appears that transferrin is involved in the transport of iron to target cells, including erythroid precursor cells 2.
From the Research
Mechanism of Iron Transport
The mechanism of iron transport from serum into the interstitial space involves the binding of iron to transferrin, a major serum iron-transport protein, and its subsequent interaction with the transferrin receptor on the cell surface 3.
Key Steps in Iron Uptake
The key steps in iron uptake by cells include:
- Binding of iron-loaded transferrin to the transferrin receptor
- Endocytosis of the receptor-ligand complex
- Release of iron from endosomal vesicles to the cytoplasm
- Storage of intracellular iron in ferritin deposits or use as a substrate for biosynthesis of haem and iron-containing proteins 3, 4, 5
Role of Transferrin Receptor
The transferrin receptor plays a crucial role in regulating iron release from transferrin, with kinetic data demonstrating that it balances the rate of iron release from each lobe of transferrin, resulting in efficient Fe(3+) release within a physiologically relevant time frame 6.
Delivery of Iron to Cells
Delivery of iron to cells is essential for cell proliferation, and the transferrin-transferrin receptor pathway is a major mechanism for iron uptake by cells 3, 5.
Iron Release from Transferrin
Iron release from transferrin bound to the transferrin receptor at endosomal pH is a critical step in iron delivery to cells, and understanding the kinetics of this process is essential for understanding iron transport and disorders 6.