The physiological functions of iron regulatory proteins in iron homeostasis - an update

Abstract

Iron regulatory proteins (IRPs) regulate the expression of genes involved in iron metabolism by binding to RNA stem-loop structures known as iron responsive elements (IREs) in target mRNAs. IRP binding inhibits the translation of mRNAs that contain an IRE in the 5′untranslated region of the transcripts, and increases the stability of mRNAs that contain IREs in the 3′untranslated region of transcripts. By these mechanisms, IRPs increase cellular iron absorption and decrease storage and export of iron to maintain an optimal intracellular iron balance. There are two members of the mammalian IRP protein family, IRP1 and IRP2, and they have redundant functions as evidenced by the embryonic lethality of the mice that completely lack IRP expression (Irp1-/-/Irp2-/- mice), which contrasts with the fact that Irp1-/- and Irp2-/- mice are viable. In addition, Irp2-/- mice also display neurodegenerative symptoms and microcytic hypochromic anemia, suggesting that IRP2 function predominates in the nervous system and erythropoietic homeostasis. Though the physiological significance of IRP1 had been unclear since Irp1-/- animals were first assessed in the early 1990s, recent studies indicate that IRP1 plays an essential function in orchestrating the balance between erythropoiesis and bodily iron homeostasis. Additionally, Irp1-/- mice develop pulmonary hypertension, and they experience sudden death when maintained on an iron-deficient diet, indicating that IRP1 has a critical role in the pulmonary and cardiovascular systems. This review summarizes recent progress that has been made in understanding the physiological roles of IRP1 and IRP2, and further discusses the implications for clinical research on patients with idiopathic polycythemia, pulmonary hypertension, and neurodegeneration.

A Glutaredoxin·BolA Complex Serves as an Iron-Sulfur Cluster Chaperone for the Cytosolic Cluster Assembly Machinery

“…Glrx3⅐[2Fe-2S]⅐BolA2 complexes may be analogous to the labile iron pool and serve to make [2Fe-2S] clusters available to apoproteins or the cytosolic [4Fe-4S] distribution machinery, essentially functioning as [2Fe-2S] cluster chaperones. The wide dynamic range and kinetic lability of the Glrx3⅐[2Fe-2S]⅐BolA2 complexes are reminiscent of the iron-sensing, iron-regulatory protein 1 (IRP1), which responds to increases in cellular iron availability by rapidly coordinating a [4Fe-4S] cluster (49,50). Cluster coordination allows IRP1 to shift from an RNA-binding protein to an enzyme; thus, IRP1 acts as an iron sensor and post-transcriptional regulator of gene expression.…”

13. Reactivity of iron-sulfur clusters with nitric oxide

“…transferrin receptor) of translation (reviewed in [209,210]. While early studies of mammalian cells lacking IRP1 or IRP2 indicated that IRP2 is the principal sensor of iron, recent studies have revealed that IRP1 plays essential functions in erythropoiesis and in pulmonary and cardiovascular systems [211].…”

Seminal Ferritin And Seminal Parameters In Patients Undergoing Chronic Hemodialysis

“…The testicular immune privilege is a complex mechanism developed in the testicular compartment to maintain the balance local of pro/anti-inflammatory cytokine levels [31], involved in regulation the synthesis of SF [32] and intracellular iron ion level via the ion regulatory protein (IRP) [33]. Mechanisms of functional interactions between germ cells and Sertoli cells; Sertoli cells and Leydig cells, known as autocrine/ paracrine regulation and hematopoietic barrier, are also part of the mechanism of testicular immune privilege protecting germ cells from effect inflammatory/oxidative/ionic toxicity [34].…”