Review
Labile iron pool: the main determinant of cellular response to oxidative stress

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Abstract

The trace amounts of “free” iron can catalyse production of a highly toxic hydroxyl radical via Fenton/Haber–Weiss reaction cycle. The critical factor appears to be the availability and abundance of cellular labile iron pool (LIP) that constitutes a crossroad of metabolic pathways of iron-containing compounds and is midway between the cellular need of iron, its uptake and storage. To avoid an excess of harmful “free” iron, the LIP is kept at the lowest sufficient level by transcriptional and posttranscriptional control of the expression of principal proteins involved in iron homeostasis. The putative sources of cellular LIP, its homeostasis and its role in the cellular response to oxidative stress are discussed.

Introduction

The unique abilities of iron to change its oxidation state and redox potential in response to the changes of liganding environment makes this metal essential for almost all living organisms. Iron-containing enzymes are the key components of many essential biological reactions, such as energy metabolism, oxygen transport, DNA synthesis and repair, detoxification of reactive oxygen species (ROS) and its reaction products and numerous other reactions catalysed by oxygenases, peroxygenases, etc. Its primary function is mediating one-electron redox reactions. However, the same biochemical properties that make iron beneficial in many biological processes might be a drawback in some particular conditions, namely, when improperly shielded iron can catalyse one-electron reductions of oxygen species that lead to production of very reactive free radicals. Trace amounts of “free” iron can catalyse production of a highly toxic hydroxyl radical via Fenton/Haber–Weiss reaction cycle. Iron-driven generation of oxygen-derived free radicals is known to induce oxidation of proteins, lipids and lipoproteins, nucleic acids, carbohydrates and other cellular components. An oxidative damage to the vital cellular components might have in turn a deleterious effect at cellular and tissue levels, leading to the cell death, tissue necrosis and degenerative diseases or cell phenotype changes and cancer formation.

Section snippets

Labile iron pool

The living organisms try to avoid an excess of “free” iron by a tight control of iron homeostasis. In most cells iron homeostasis is a few-stage process consisting of iron uptake, utilisation and storage. The principal effectors of this process are transferrin receptor (TFR) and divalent metal transporter 1 (DMT1, also DCT1; NRAMP2), proteins involved in iron uptake, and ferritin (FT), an iron-sequestering protein. Since different proteins carry out uptake and storage of iron, there is a pool

Quantification of LIP in living cells

Based on the experimental approach, methods for the determination of LIP can be divided into two main groups: the methods that require disruption of cell integrity and fractionation of cellular components and the methods that enable measurements in intact cells. The disruptive methods usually require subfractionation of cellular components into several fractions of different molecular weight and subsequent quantification of iron content in each fraction. The major disadvantage of these

The role of LIP in the cellular response to oxidative stress

LIP level is midway between the cellular need for iron and the hazard of excessive generation of hydroxyl radical. It has been proposed that LIP is a cellular source of iron ions available for Fenton reaction [49]. In the presence of H2O2, iron catalyses generation of very reactive hydroxyl radical (radical dotOH) (Eq. (1)). The oxidised metal is reduced by cellular reducing equivalents, such as superoxide (O2radical dot), allowing the next turn of reaction (Eq. (2)). The summary reaction is called Haber–Weiss

Summary

Iron-driven Fenton/Haber–Weiss reaction gives rise to the toxic reactive oxygen species. Thus, “free” iron must be kept at the lowest acceptable level to prevent the hazard of oxidative stress. On the other hand, there is a physiological demand of easily accessible iron that can be incorporated to the plethora of iron-containing proteins. The critical point in understanding the mechanism of iron homeostasis in mammalian cells has been the practical demonstration of the existence of a transient

Acknowledgements

This work was supported by KBN grant 6 P04A 064 20. The author is grateful to Dr. P. Lipiński and Prof. I. Szumiel for helpful discussion.

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