Rouault, T. A. The role of iron regulatory proteins in mammalian iron homeostasis and disease. Nat. Chem. Biol. 2, 406-414

Cell Biology and Metabolism Branch, National Institute of Child Health and Human Development, Building 18T, Room 101, National Institutes of Health, Bethesda, Maryland 20892, USA.
Nature Chemical Biology (Impact Factor: 13). 09/2006; 2(8):406-14. DOI: 10.1038/nchembio807
Source: PubMed

ABSTRACT Iron regulatory proteins 1 and 2 (IRP1 and IRP2) are mammalian proteins that register cytosolic iron concentrations and post-transcriptionally regulate expression of iron metabolism genes to optimize cellular iron availability. In iron-deficient cells, IRPs bind to iron-responsive elements (IREs) found in the mRNAs of ferritin, the transferrin receptor and other iron metabolism transcripts, thereby enhancing iron uptake and decreasing iron sequestration. IRP1 registers cytosolic iron status mainly through an iron-sulfur switch mechanism, alternating between an active cytosolic aconitase form with an iron-sulfur cluster ligated to its active site and an apoprotein form that binds IREs. Although IRP2 is homologous to IRP1, IRP2 activity is regulated primarily by iron-dependent degradation through the ubiquitin-proteasomal system in iron-replete cells. Targeted deletions of IRP1 and IRP2 in animals have demonstrated that IRP2 is the chief physiologic iron sensor. The physiological role of the IRP-IRE system is illustrated by (i) hereditary hyperferritinemia cataract syndrome, a human disease in which ferritin L-chain IRE mutations interfere with IRP binding and appropriate translational repression, and (ii) a syndrome of progressive neurodegenerative disease and anemia that develops in adult mice lacking IRP2. The early death of mouse embryos that lack both IRP1 and IRP2 suggests a central role for IRP-mediated regulation in cellular viability.

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    • "In the absence of iron, IRP1 and IRP2 bind to iron responsive elements (IREs) present in the 5 0 or 3 0 untranslated regions (UTRs) of the mRNAs encoding these proteins. This binding prevents or promotes translation of the encoded proteins (Hentze et al., 2010; Muckenthaler et al., 2008; Rouault, 2006). For example, the translation of the iron storage protein ferritin is regulated by IRP binding to an IRE present in the 5 0 UTR of the mRNA (Hentze et al., 1987). "
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    ABSTRACT: During its parasitic life stages, the marine ectoparasitic copepod Lepeophtheirus salmonis ingests large amounts of host blood, which contains high amounts of iron. Iron is an essential micronutrient, but also toxic in high dosages, and blood-feeding parasites like the salmon louse must thus possess an efficient system to handle the excess iron. Iron regulatory protein 1 and 2 (IRP1 and IRP2) are known to play crucial roles in this process, by regulating several proteins involved in iron transport and storage, depending on the cellular iron concentration. To gain knowledge about the regulation of the iron metabolism in salmon lice, two IRP homologues (LsIRP1A and LsIRP1B) were identified by sequence and predicted structure similarity to known IRPs in other species. In situ hybridisation revealed that LsIRP1A and LsIRP1B mRNAs were expressed in the ovaries, oviducts and vitellogenic oocytes of adult females. Transcription levels of LsIRP1A and LsIRP1B mRNAs did not differ significantly between the different developmental stages of the salmon louse. Adults in the absence of blood as a feed source had decreased levels of LsIRP1A, but not LsIRP1B mRNA. RNA binding experiments indicated the presence of functioning IRP in salmon lice. In order to explore the biological functions of LsIRP1A and LsIRP1B, the mRNAs of both proteins were knocked down by RNA interference (RNAi) in preadult females. The knockdown was confirmed by qRT-PCR. LsIRP1B knockdown lice produced less offspring than control lice due to slightly shorter egg strings and had decreased levels of transcripts involved in egg development. Knockdown of both LsIRP1A and LsIRP1B caused increased expression of a salmon louse Ferritin (LsFer). These results confirm that salmon lice have two IRP1 homologues, LsIRP1A and LsIRP1B, and might suggest a function in cellular iron regulation in the reproductive organs and eggs. Copyright © 2015. Published by Elsevier Inc.
    Experimental Parasitology 06/2015; 157. DOI:10.1016/j.exppara.2015.06.010 · 1.64 Impact Factor
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    • "Low cytosolic iron levels cause two homologous IRPs (IRP1 and IRP2) to inhibit Ft and Fpn-1 translation and to stabilize mRNA transcripts of TfR and divalent metal transporter 1 (DMT1) [26]. In iron replete cells, neither IRP1 nor IRP2 binds IREs and Ft/Fpn-1 expression increases while TfR/DMT1 expression decreases [27]. After SAH, a large amount of iron arising from hemoglobin degradation was released into the subarachnoid space and more iron was transported into the cells. "
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    ABSTRACT: Previous studies have shown that iron accumulation is involved in the pathogenesis of brain injury following subarachnoid hemorrhage (SAH) and chelation of iron reduced mortality and oxidative DNA damage. We previously reported that blockage of mitochondrial calcium uniporter (MCU) provided benefit in the early brain injury after experimental SAH. This study was undertaken to identify whether blockage of MCU could ameliorate iron accumulation-associated brain injury following SAH. Therefore, we used two reagents ruthenium red (RR) and spermine (Sper) to inhibit MCU. Sprague-Dawley (SD) rats were randomly divided into four groups including sham, SAH, SAH+RR, and SAH+Sper. Biochemical analysis and histological assays were performed. The results confirmed the iron accumulation in temporal lobe after SAH. Interestingly, blockage of MCU dramatically reduced the iron accumulation in this area. The mechanism was revealed that inhibition of MCU reversed the down-regulation of iron regulatory protein (IRP) 1/2 and increase of ferritin. Iron-sulfur cluster dependent-aconitase activity was partially conserved when MCU was blocked. In consistence with this and previous report, ROS levels were notably reduced and ATP supply was rescued; levels of cleaved caspase-3 dropped; and integrity of neurons in temporal lobe was protected. Taken together, our results indicated that blockage of MCU could alleviate iron accumulation and the associated injury following SAH. These findings suggest that the alteration of calcium and iron homeostasis be coupled and MCU be considered to be a therapeutic target for patients suffering from SAH. Copyright © 2014. Published by Elsevier Inc.
    Biochemical and Biophysical Research Communications 12/2014; 456(4). DOI:10.1016/j.bbrc.2014.12.073 · 2.30 Impact Factor
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    • "The mechanisms by which Mg 2+ concentration is regulated at the cellular level and the effects in human health has still been poorly understood due to the scarcity of efficient chemical tools for the study of this ion. Similarly, Fe 3+ serves as a cofactor for many proteins and enzymes that are required for oxygen and energy metabolism, as well as for several other essential processes [8] [9]. Fe 3+ deficiency is the most common cause of anemia in the world [10]. "
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    ABSTRACT: A new Schiff base ligand based on triphenylamine (1) was synthesized and demonstrated solvent dependent selective fluorescence sensing of Mg2+ and Fe3+ ions up to ppm level (10(-6) M). Highly selective turn-on fluorescence for Mg2+ was observed in DMSO as well as DMF (lambda(max) = 506 nm, Phi = 0.007 (1), 0.17 (1 + Mg2+)). Interestingly, in THF, 1 showed strong turn-on fluorescence for Fe3+ (blue, lambda(max) = 460 nm, Phi = 0.064) as well as for Mg2+ (greenish yellow). Interference studies confirm that Ca2+ that strongly competes with mg(2+) sensing had negligible interference. The practical application of 1 for selective fluorescence sensing of Mg2+ from different water samples has also been demonstrated.
    Inorganic Chemistry Communications 10/2014; 48. DOI:10.1016/j.inoche.2014.08.003 · 1.78 Impact Factor
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