Entry of iron into cells: A new role for the transferrin receptor in modulating iron release from transferrin

Abstract The versatile chemistry of iron and the noxious reactions this essential metal may promote have compelled iron‐dependent organisms to form specific iron‐binding proteins to maintain iron in soluble, nontoxic, and accessible form for cellular needs. A variety of pathways can be traversed by iron to gain access to cells, some available to all cells, others restricted to specialized cells. Of these pathways, the most important and widely functioning is uptake of iron from transferrin in a receptor‐mediated process. By regulating expression of the transferrin receptor, iron‐dependent cells, including neurons, can be assured an adequate supply of the essential metal while guarding against toxic excess. However, the transferrin receptor functions not only in capturing iron‐bearing transferrin, but also in restraining release of iron from transferrin at the cell surface, where iron‐catalyzed lipid peroxidation is a threat, while facilitating iron release in acidified endosomes to ensure safe and efficient delivery to the cell.