The iron regulatory proteins: targets and modulators of free radical reactions and oxidative damage,

doi:10.1016/S0891-5849(02)00825-0

Free Radical Biology and Medicine

Volume 32, Issue 12, 15 June 2002, Pages 1237-1243

https://doi.org/10.1016/S0891-5849(02)00825-0 Get rights and content

Abstract

Iron acquisition is a fundamental requirement for many aspects of life, but excess iron may result in formation of free radicals that damage cellular constituents. For this reason, the amount of iron within the cell is carefully regulated in order to provide an adequate level of a micronutrient while preventing its accumulation and toxicity. A major mechanism for the regulation of iron homeostasis relies on the post-transcriptional control of ferritin and transferrin receptor mRNAs, which are recognized by two cytoplasmic iron regulatory proteins (IRP-1 and IRP-2) that modulate their translation and stability, respectively. IRP-1 can function as a mRNA binding protein or as an aconitase, depending on whether it disassembles or assembles an iron-sulfur cluster in response to iron deficiency or abundancy, respectively. IRP-2 is structurally and functionally similar to IRP-1, but does not assemble a cluster nor exhibits aconitase activity. Here we briefly review the role of IRP in iron-mediated damage induced by oxygen radicals, nitrogen-centered reactive species, and xenobiotics of pharmacological and clinical interest.

Introduction

Iron is essential for a broad number of physiologic functions, varying from oxygen transport and utilization to DNA synthesis and xenobiotic detoxification. In order to execute such multiple tasks iron must be incorporated in the heme moieties of hemoglobin, myoglobin, and cytochromes; alternatively, iron can bind to enzymes in a form of nonheme moieties (e.g., in ribonucleotide reductase) or Fe-S motifs (such as those associated with several mitochondrial enzymes). Anytime iron exceeds the metabolic needs of the cell it may form a low molecular weight pool, tentatively referred to as the labile iron pool (LIP), which converts normal by-products of cell respiration, like superoxide anion (O₂^•−) and hydrogen peroxide (H₂O₂), into highly damaging hydroxyl radicals or equally aggressive ferryl ions or oxygen-bridged Fe(II)/Fe(III) complexes. Thus, iron is a janus element that can be both good and bad to the cell, depending on whether it serves as a micronutrient or as a catalyst of free radical reactions. It is because of such a dual function of iron that cells have evolved coordinate mechanisms to maintain LIP within physiological values. Here we will briefly discuss the role that iron regulatory proteins (IRP) may play in this context, as molecular targets and modulators of oxidative damage. An in-depth coverage of the fine structure and function of IRP can be found in other recently published reviews [1], [2], [3], [4].

Section snippets

Role of IRP-1 and IRP-2 in the maintenance of intracellular iron homeostasis

The last decades have witnessed significant progress in the molecular characterization of iron homeostasis. Expression of transferrin receptor (TfR), which mediates iron uptake by internalizing iron-laden transferrin, is increased when cells are iron-depleted. On the other hand, expression of ferritin (Ft), which sequesters iron, is increased when iron levels are high. Concerted regulation of these two proteins presumably ensures that LIP never exceeds cellular needs and defense systems.

IRP as direct targets of oxygen free radicals: a protective stratagem against oxidative damage

Studies in rat liver lysates have shown that H₂O₂ or O₂^•− alone lacked reactivity toward IRP-1, but a combined action of the two species induced reversible inactivation of IRP-1 [23]. Such an effect was attributed to direct interactions of O₂^•− and H₂O₂ with a preformed pool of IRP-1, resulting in reversible modifications of -SH residues that mediate IRE recognition (e.g., cys⁴³⁷). IRP inactivation was subsequently observed in murine fibroblasts exposed to menadione, a quinone compound that

IRP as direct or indirect targets of reactive nitrogen species: relevance to iron metabolism and macrophage function

Iron sulfur clusters have long been recognized as molecular targets of nitric oxide ( radical dot NO). Therefore, several studies have addressed whether NO, generated by endogenous synthases or exogenous donors, may influence iron metabolism by attacking the [4Fe–4S] cluster of cytoplasmic aconitase/IRP-1. Several reports have shown that NO does increase IRP-1 activity, but the precise mechanism(s) of such activation have remained unclear. Some investigators suggested that radical dot NO attacked the Fe-S cluster of

IRP and iron-mediated damage in a pharmacologic setting: the case of doxorubicin-induced cardiotoxicity

Doxorubicin (DOX)-induced cardiotoxicity provides an excellent model to appraise the role of IRP in iron-mediated toxicity in a pharmacologic setting. DOX is an anthracycline antibiotic with activity in a broad spectrum of human tumors, but also causes a severe form of chronic cardiomyopathy, resulting in heart failure. One-electron redox cycling of a quinone moiety in the tetracyclic ring of DOX reduces molecular oxygen to O₂^•− and H₂O₂ while also releasing iron from Ft. Thus, redox activation

Conclusions and perspectives

We have briefly reviewed the role of IRP in iron-mediated damage induced by ROS, RNS, and certain xenobiotics of biomedical interest. Whereas the intimate mechanisms through which IRP prevent or amplify cell damage under such conditions call for further investigations, available data suggest that these proteins should be regarded as important determinants of cellular responses, due to their central role in coordinating iron trafficking. The paradigm of DOX-induced cardiotoxicity also

Acknowledgements

This work was supported by grants from MURST COFIN 2000 and 2001 (G.C., A.P., G.M.); Associazione Italiana Ricerca sul Cancro (G.C., G.M.); MURST Center of Excellence on Aging at the University of Chieti (G.M).

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¹: Guest Editor: Mario Comporti

²: This article is part of a series of reviews on “Iron and Cellular Redox Status.” The full list of papers may be found on the homepage of the journal.

³: Gaetano Cairo received his Ph.D. degree at the University of Pavia and is presently Professor at the University of Milano School of Medicine, where he studies iron proteins gene expression under pathophysiological conditions. Stefania Recalcati, M.D. and gastroenterologist, is presently a Ph.D. student at the University of Milano where she investigates the molecular basis of iron disorders. Antonello Pietrangelo, M.D., Ph.D., and gastroenterologist, worked on liver specific gene expression as postdoctoral fellow at the Albert Einstein College of Medicine and is presently Professor at the University of Modena School of Medicine, where he continues his studies on hemochromatosis and iron-mediated cell damage.

⁴: Giorgio Minotti, M.D. and oncologist, developed interest in the role of iron in free radical reactions during a postdoctoral stage in Dr. Aust’s laboratory at Michigan State University. He is presently Professor at the University of Chieti School of Medicine, where he continues his research on the role of iron in anthracycline cardiotoxicity.

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Serial review: iron and cellular redox statusThe iron regulatory proteins: targets and modulators of free radical reactions and oxidative damage1, 2

Abstract

Introduction

Section snippets

Role of IRP-1 and IRP-2 in the maintenance of intracellular iron homeostasis

IRP as direct targets of oxygen free radicals: a protective stratagem against oxidative damage

IRP as direct or indirect targets of reactive nitrogen species: relevance to iron metabolism and macrophage function

IRP and iron-mediated damage in a pharmacologic setting: the case of doxorubicin-induced cardiotoxicity

Conclusions and perspectives

Acknowledgements

Biochem. Pharmacol.

J. Biol. Chem.

Blood

J. Biol. Chem.

Mol. Cell.

J. Biol. Chem.

J. Biol. Chem.

Blood

J. Biol. Chem.

J. Biol. Chem.

J. Biol. Chem.

Gastroenterology

Blood

J. Biol. Chem.

J. Biol. Chem.

Biochim. Biophys. Acta

J. Biol. Chem.

J. Biol. Chem.

Methods

J. Biol. Chem.

Blood

Molecular control of vertebrate iron metabolismmRNA-based regulatory circuits operated by iron, nitric oxide, and oxidative stress

Proc. Natl. Acad. Sci. USA

Regulation of the iron regulatory proteins by reactive nitrogen and oxygen species

Gene Expr.

Iron regulatory proteins in pathobiology

Biochem. J.

HIF-1-mediated activation of transferrin receptor gene transcription by iron chelation

Nucleic Acids Res.

Ultraviolet A radiation induces immediate release of iron in human primary skin fibroblaststhe role of ferritin

Proc. Natl. Acad. Sci. USA

Serial review: iron and cellular redox status
The iron regulatory proteins: targets and modulators of free radical reactions and oxidative damage1, 2