Mutation Research/Fundamental and Molecular Mechanisms of Mutagenesis
ReviewLabile iron pool: the main determinant of cellular response to oxidative stress
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 (OH) (Eq. (1)). The oxidised metal is reduced by cellular reducing equivalents, such as superoxide (O2), 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.
References (94)
- et al.
A labile iron pool
J. Biol. Chem.
(1946) - et al.
The labile iron pool: characterization, measurement, and participation in cellular processes
Free Radic. Biol. Med.
(2002) - et al.
Iron acquired from transferrin by K562 cells is delivered into a cytoplasmic pool of chelatable iron(II)
J. Biol. Chem.
(1995) - et al.
Cellular and subcellular localization of the Nramp2 iron transporter in the intestinal brush border and regulation by dietary iron
Blood
(1999) - et al.
Molecular and functional roles of duodenal cytochrome B (dcytb) in iron metabolism
Blood Cells Mol. Dis.
(2002) - et al.
Defective iron uptake and globin synthesis by erythroid cells in the anemia of the Belgrade laboratory rat
Blood
(1978) - et al.
Role of ferritin in the control of the labile iron pool in murine erythroleukemia cells
J. Biol. Chem.
(1998) - et al.
Overexpression of wild type and mutated human ferritin H-chain in HeLa cells: in vivo role of ferritin ferroxidase activity
J. Biol. Chem.
(2000) - et al.
Regulation of intracellular iron metabolism in human erythroid precursors by internalized extracellular ferritin
Blood
(1999) - et al.
The cellular labile iron pool and intracellular ferritin in K562 cells
Blood
(1999)
Ferritin iron kinetics and protein turnover in K562 cells
J. Biol. Chem.
Hemopexin: a review of biological aspects and the role in laboratory medicine
Clin. Chim. Acta
Hyperbilirubinemia results in reduced oxidative injury in neonatal Gunn rats exposed to hyperoxia
Free Radic. Biol. Med.
Heme oxygenase activity causes transient hypersensitivity to oxidative ultraviolet A radiation that depends on release of iron from heme
Free Radic. Biol. Med.
Human cytoplasmic aconitase (iron regulatory protein 1) is converted into its [3Fe–4S] form by hydrogen peroxide in vitro but is not activated for iron-responsive element binding
J. Biol. Chem.
An EPR investigation of the products of the reaction of cytosolic and mitochondrial aconitases with nitric oxide
J. Biol. Chem.
Nitric oxide and peroxynitrite-dependent aconitase inactivation and iron-regulatory protein-1 activation in mammalian fibroblasts
Arch. Biochem. Biophys.
A novel mammalian iron-regulated protein involved in intracellular iron metabolism
J. Biol. Chem.
A novel duodenal iron-regulated transporter, IREG1, implicated in the basolateral transfer of iron to the circulation
Mol. Cell.
Nitrogen monoxide (no) and glucose: unexpected links between energy metabolism and no-mediated iron mobilization from cells
J. Biol. Chem.
Fluorescence analysis of the labile iron pool of mammalian cells
Anal. Biochem.
Intracellular iron status as a hallmark of mammalian cell susceptibility to oxidative stress: a study of L5178Y mouse lymphoma cell lines differentially sensitive to H(2)O(2)
Blood
Antioxidant enzyme gene transcription in copper-deficient rat liver
Free Radic. Biol. Med.
Newly delivered transferrin iron and oxidative cell injury
FEBS Lett.
Oxidative damage to DNA constituents by iron-mediated fenton reactions. The deoxyguanosine family
J. Biol. Chem.
Iron homeostasis, oxidative stress, and DNA damage
Free Radic. Biol. Med.
Iron and oxidative stress in bacteria
Arch. Biochem. Biophys.
Iron metabolism, free radicals, and oxidative injury
Biomed. Pharmacother.
Oxidative DNA damage mediated by copper(II), iron(II) and nickel(II) fenton reactions: evidence for site-specific mechanisms in the formation of double-strand breaks, 8-hydroxydeoxyguanosine and putative intrastrand cross-links
Mutat. Res.
Iron is the intracellular metal involved in the production of DNA damage by oxygen radicals
Mutat. Res.
Comparison of effects of iron and calcium chelators on the response of L5178Y sublines to X-rays and H2O2
Mutat. Res.
Intracellular iron, but not copper, plays a critical role in hydrogen peroxide-induced DNA damage
Free Radic. Biol. Med.
Iron ion induces mitochondrial DNA damage in HTC rat hepatoma cell culture—role of antioxidants in mitochondrial DNA protection from oxidative stresses
Arch. Biochem. Biophys.
H-ferritin subunit overexpression in erythroid cells reduces the oxidative stress response and induces multidrug resistance properties
Blood
Repression of ferritin expression increases the labile iron pool, oxidative stress, and short-term growth of human erythroleukemia cells
Blood
Hemin-enhanced resistance of human leukemia cells to oxidative killing: antisense determination of ferritin involvement
Arch. Biochem. Biophys.
Lipid hydroperoxide generation, turnover, and effector action in biological systems—review
J. Lipid Res.
Lipid peroxidation and protein modification in a mouse model of chronic iron overload
Metabolism
The iron chelator pyridoxal isonicotinoyl hydrazone inhibits mitochondrial lipid peroxidation induced by Fe(II)-citrate
Eur. J. Pharmacol.
Further evidence that oxidative stress may be a risk factor responsible for the development of atherosclerosis
Free Radic. Biol. Med.
Cell-mediated reduction of protein and peptide hydroperoxides to reactive free radicals
Free Radic. Biol. Med.
The basic chemistry of nitrogen monoxide and peroxynitrite
Free Radic. Biol. Med.
Translational pathophysiology: a novel molecular mechanism of human disease
Blood
Nramp 2 (DCT1/DMT1) expressed at the plasma membrane transports iron and other divalent cations into a calcein-accessible cytoplasmic pool
J. Biol. Chem.
Antiproliferative and apoptotic effects of iron chelators on human cervical carcinoma cells
Gynecol. Oncol.
Cellular non-heme iron content is a determinant of nitric oxide-mediated apoptosis, necrosis, and caspase inhibition
J. Biol. Chem.
Overexpression of the ferritin H subunit in cultured erythroid cells changes the intracellular iron distribution
Blood
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