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. Introduction Overview of Iron Homeostasis Systemic iron metabolism Iron absorption Iron distribution and recycling within the body Regulation Cell iron metabolism The IRE/IRP Regulatory System Structure and general regulation of IRPs IRP1 IRP2 Iron responsive elements Role of the IRE–IRP regulatory network in iron uptake Role of the IRE–IRP regulatory network in iron storage Role of the IRE–IRP regulatory network in iron release Role of the IRE–IRP regulatory network in other pathways Roles and importance of IRP1 and IRP2 Regulation of IRP Function by Stimuli Other than Iron Hypoxia Oxidative stress Reactive nitrogen species Xenobiotics Cell growth Others Role of IRPs in Physiology and Disease Effects of IRP1 and IRP2 deficiency IRP-related clinical situations Pharmacological Modulation of Iron-Mediated Oxidative Damage Conclusions and Future Directions