Mammalian iron metabolism and its control by iron regulatory proteins

Cellular iron homeostasis is maintained by iron regulatory proteins 1 and 2 (IRP1 and IRP2). IRPs bind to iron-responsive elements (IREs) located in the untranslated regions of mRNAs encoding protein involved in iron uptake, storage, utilization and export. Over the past decade, significant progress has been made in understanding how IRPs are regulated by iron-dependent and iron-independent mechanisms and the pathological consequences of IRP2 deficiency in mice. The identification of novel IREs involved in diverse cellular pathways has revealed that the IRP–IRE network extends to processes other than iron homeostasis. A mechanistic understanding of IRP regulation will likely yield important insights into the basis of disorders of iron metabolism. This article is part of a Special Issue entitled: Cell Biology of Metals.

► IRP1 and IRP2 are the principal regulators of mammalian cellular iron homeostasis.
► IRPs bind to iron-responsive elements (IREs) located in the untranslated regions of mRNAs involved in iron uptake, storage, utilization and export.
► IRPs are post-translationally regulated by iron and reactive oxygen and nitrogen species.
► The identification of novel IREs reveals the presence of an expanded IRP–IRE network beyond cellular iron homeostasis.
► IRP deficiency in mice disrupts iron homeostasis and leads to hematological, neurodegenerative and metabolic disorders.