Iron Regulatory Proteins: From Molecular Mechanisms to Drug Development

Eukaryotic cells require iron for survival but, as an excess of poorly liganded iron can lead to the catalytic production of toxic radicals that can damage cell structures, regulatory mechanisms have been developed to maintain appropriate cell and body iron levels. The interactions of iron responsive elements (IREs) with iron regulatory proteins (IRPs) coordinately regulate the expression of the genes involved in iron uptake, use, storage, and export at the post-transcriptional level, and represent the main regulatory network controlling cell iron homeostasis. IRP1 and IRP2 are similar (but not identical) proteins with partially overlapping and complementary functions, and control cell iron metabolism by binding to IREs (i.e., conserved RNA stem-loops located in the untranslated regions of a dozen mRNAs directly or indirectly related to iron metabolism). The discovery of the presence of IREs in a number of other mRNAs has extended our knowledge of the influence of the IRE/IRP regulatory network to new metabolic pathways, and it has been recently learned that an increasing number of agents and physiopathological conditions impinge on the IRE/IRP system. This review focuses on recent findings concerning the IRP-mediated regulation of iron homeostasis, its alterations in disease, and new research directions to be explored in the near future. Antioxid. Redox Signal. 13, 1593-1616.