Transferrin Receptor Dynamics in Cellular Iron Uptake
Summary
Iron is essential for cellular respiration, DNA synthesis and numerous enzymatic reactions. Its transport in vertebrates relies on the iron‐binding glycoprotein transferrin, which circulates in plasma and donates iron to cells via specific transferrin receptors (TfR) displayed on the plasma membrane. The process begins with diferric transferrin binding to TfR, followed by clathrin‐mediated endocytosis into early endosomes. Endosomal acidification (pH ≈ 5.5) triggers iron release from transferrin, after which iron crosses the endosomal membrane into the cytosol for incorporation into ferritin or haem proteins. Apotransferrin remains bound to TfR and is recycled back to the cell surface, where neutral pH promotes its dissociation. This cycle—uniquely efficient in many cell types—ensures rapid iron uptake while preserving receptor integrity. Regulation of TfR expression and endosomal trafficking is finely tuned by intracellular iron levels, growth factors and stress signals, underscoring the receptor’s central role in iron homoeostasis, cell proliferation and pathology such as anaemia, neurodegeneration and cancer.
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Technical terms
Transferrin: Iron‐binding glycoprotein that transports ferric ions in blood plasma.
Transferrin receptor (TfR): Membrane protein that specifically binds transferrin and mediates its internalisation via endocytosis.
Endocytosis: Energy‐dependent process by which cells internalise extracellular ligands and receptors into vesicles.
Endosome: Intracellular vesicle where acidification induces conformational changes in transferrin leading to iron release.
Lysosomotropic agent: Compound that raises vesicular pH, thereby inhibiting acid‐dependent dissociation of iron from transferrin.
References
- Kinetics of internalization and recycling of transferrin and the transferrin receptor in a human hepatoma cell line. Effect of lysosomotropic agents.. Journal of Biological Chemistry (1983).
- Receptor-mediated endocytosis of transferrin in K562 cells.. Journal of Biological Chemistry (1983).
- The kinetics of transferrin endocytosis and iron uptake from transferrin in rabbit reticulocytes.. Journal of Biological Chemistry (1983).
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