Abstract
Iron has outstanding biological importance as it is required for a wide variety of essential cellular processes and, as such, is a vital nutrient. The element holds this central position by virtue of its facile redox chemistry and the high affinity of both redox states (iron II and iron III) for oxygen. These same properties also render iron toxic when its redox-active chelatable ‘labile’ form exceeds the normal binding capacity of the cell. Indeed, in contrast to iron bound to proteins, the intracellular labile iron (LI) can be potentially toxic especially in the presence of reactive oxygen species (ROS), as it can lead to catalytic formation of oxygen-derived free radicals such as hydroxyl radical that ultimately overwhelm the cellular antioxidant defense mechanisms and lead to cell damage. While intracellular iron homeostasis and body iron balance are tightly regulated to minimise the presence of potentially toxic LI, under conditions of oxidative stress and certain pathologies, iron homeostasis is severely altered. This alteration manifests itself in several ways, one of which is an increase in the intracellular level of potentially harmful LI. For example acute exposure of skin cells to ultraviolet A (UVA, 320–400 nm), the oxidising component of sunlight provokes an immediate increase in the available pool of intracellular LI that appears to play a key role in the increased susceptibility of skin cells to UVA-mediated oxidative membrane damage and necrotic cell death. The main purpose of this overview is to bring together some of the new findings related to intracellular LI distribution and trafficking under physiological and patho-physiological conditions as well as to discuss mechanisms and consequences of oxidant-induced alterations in the intracellular pool of LI, as exemplified by UVA radiation.
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References
G. Cairo, F. Bernuzzi, S. Recalcati, A precious metal: Iron, an essential nutrient for all cells, Genes Nutr., 2006, 1, 25–39
N. T. Le, D. R. Richardson, The role of iron in cell cycle progression and the proliferation of neoplastic cells, Biochim. Biophys. Acta, 2002, 1603, 31–46.
D. R. Richardson, P. Ponka, The molecular mechanisms of the metabolism and transport of iron in normal and neoplastic cells, Biochim. Biophys. Acta, 1997, 1331, 1–40.
O. Kakhlon, Z. I. Cabantchik, The labile iron pool: Characterization, measurement and participation in cellular processes, Free Radical Biol. Med., 2002, 33, 1037–1046.
B. Halliwell, J. M. C. Gutteridge, Biologically relevant metal ion-dependent hydroxyl radical generation: An update, FEBS Lett., 1992, 307, 108–112.
R. M. Tyrrell, The molecular and cellular pathology of solar ultraviolet radiation, Mol. Aspects Med., 1994, 15, 1–77.
R. M. Tyrrell, Activation of mammalian gene expression by the UV component of sunlight-from models to reality, BioEssays, 1996, 18, 139–148.
H. J. Danpure, R. M. Tyrrell, Oxygen dependence of near-UV (365 nm) lethality and the interaction of near-UV and X-rays in two mammalian cell lines, Photochem. Photobiol., 1976, 23, 171–177.
R. M. Tyrrell, in Oxidative Stress: Oxidants and Antioxidants, ed. H. Sies, Academic Press, London, 1991, pp 57–83.
C. Beauchamp, I. A. Fridovich, A mechanism for the production of ethylene from methional. The generation of the hydroxyl radical by xanthine oxidase, J. Biol. Chem., 1970, 245, 4641–4646.
J. A. Badwey, M. L. Karnovsky, Active oxygen species and the functions of phagocytic leukocytes, Annu. Rev. Biochem., 1980, 49, 695–726.
A. Valencia, I. E. Kochevar, Nox1-based NADPH oxidase is the major source of UVA-induced reactive oxygen species in human keratinocytes, J. Invest. Dermatol., 2007, 128, 214–222.
R. M. Tyrrell, M. Pidoux, Correlation between endogenous glutathione content and sensitivity of cultured human skin cells to radiation at defined wavelengths in the solar UV range, Photochem. Photobiol., 1988, 47, 405–412.
C. Pourzand, R. D. Watkin, J. E. Brown, R. M. Tyrrell, Ultraviolet A radiation induces immediate release of iron in human primary skin fibroblasts: The role of ferritin, Proc. Natl. Acad. Sci. U. S. A., 1999, 96, 6751–6756.
E. Kvam, A. Noel, S. Basu-Modak, R. M. Tyrrell, Cyclooxygenase dependent release of heme from microsomal hemeproteins correlates with induction of heme oxygenase 1 transcription in human fibroblasts, Free Radical Biol. Med., 1999, 26, 511–517.
R. M. Tyrrell, Solar ultraviolet A radiation: An oxidizing skin carcinogen that activates heme oxygenase-1, Antioxid. Redox Signal., 2004, 6, 835–840.
G. F. Vile, R. M. Tyrrell, UVA radiation-induced oxidative damage to lipids and proteins in vitro and in human skin fibroblasts is dependent on iron and singlet oxygen, Free Radical Biol. Med., 1995, 18, 721–730.
R. M. Tyrrell, V. E. Reeve, Potential protection of skin by acute UVA irradiation-from cellular to animal models, Prog. Biophys. Mol. Biol., 2006, 92, 86–91.
C. J. Bertling, F. Lin, A. W. Girotti, Role of hydrogen peroxide in the cytotoxic effects of UVA/B radiation on mammalian cells, Photochem. Photobiol., 1996, 64, 137–142.
G. T. Wondrak, M. K. Jacobson, E. L. Jacobson, Endogenous UVA-photosensitizers: mediators of skin photodamage and novel targets for skin photoprotection, Photochem. Photobiol. Sci., 2006, 5, 215–237.
P. Morliere, A. Moysan, R. Santus, G. Huppe, J-C Maziere, L. Ertret, UVA-induced lipid peroxidation in cultured human fibroblasts, Biochim. Biophys. Acta, 1991, 1084, 261–268.
K. Punnonen, C. T. Jansen, A. Puntala, M. Ahotoupa, Effects of ultraviolet A and B irradiation on lipid peroxidation and activity of the antioxidant enzymes in keratinocytes in culture, J. Invest. Dermatol., 1991, 96, 255–259.
J. Dissemond, L. A. Schneider, P. Brenneisen, K. Briviba, J. Wenk, M. Wlaschek, K. Scharfetter-Kochanek, Protective and determining factors for the overall lipid peroxidation in ultraviolet A1-irradiated fibroblasts: in vitro and in vivo investigations, Br. J. Dermatol., 2003, 149, 341–349.
S. D. Aust, L. A. Morehouse, C. E. Thomas, Role of metals in oxygen radical reactions, J. Free Radicals Biol. Med., 1985, 1, 3–25.
A. W. Girotti, Photosensitized oxidation of membrane lipids: reaction pathways, cytotoxic effects, and cytoprotective mechanisms, J. Photochem. Photobiol., B, 2001, 63, 103–113.
O. Reelfs, I. M. Eggleston, C. Pourzand, Skin protection against UVA-induced iron damage by multiantioxidants and iron chelating drugs/prodrug, Curr. Drug Metab., 2010, 11, 242–249.
C. Pourzand, R. M. Tyrrell, Apoptosis, the role of oxidative stress and the example of solar ultraviolet radiation, Photochem. Photobiol., 1999, 70, 380–391.
J. L. Zhong, A. Yiakouvaki, P. Holley, R. M. Tyrrell, C. Pourzand, Susceptibility of skin cells to UVA-induced necrotic cell death reflects the intracellular level of labile iron, J. Invest. Dermatol., 2004, 123, 771–780.
K. Scharfetter-Kochanek, M. Wlaschek, P. Brenneisen, M. Scauen, R. Blaudschun, J. Wenk, UV-induced reactive oxygen species in photocarcinogenesis and photoaging, Biol. Chem., 1997, 378, 1247–1257.
M. Shayeghi, G. O. Latunde-Dada, J. S. Oakhill, A. H. Laftah, K. Takeuchi, N. Halliday, Y. Khan, A. Warley, F. E. McCann, R. C. Hider, D. M. Frazer, G. J. Anderson, C. D. Vulpe, R. J. Simpson, A. T. McKie, Identification of an intestinal heme transporter, Cell, 2005, 122, 789–801.
N. C. Andrews, Molecular control of iron metabolism, Best Pract. Res. Clin. Haematol., 2005, 18, 159–169.
C. W. Trenam, D. R. Blake, C. J. Morris, Skin inflammation: Reactive oxygen species and the role of iron, J. Invest. Dermatol., 1992, 99, 675–682.
L. C. Kuhn, Molecular regulation of iron proteins, Bailliere’s Clin. Haematol., 1994, 7, 763–785.
R. Crichton, B. Danielson and P. Geisser, in Iron therapy with special emphasis on intravenous administration (4th Edition), UNI-MED, Bremen, Germany, 2008, pp. 14–16.
T. Ganz, Molecular control of iron transport, J. Am. Soc. Nephrol., 2007, 18, 394–400.
S. Epsztejn, O. Kakhlon, H. Glickstein, W. Breuer, Z. I. Cabantchik, Fluorescence analysis of the labile iron pool of mammalian cells, Anal. Biochem., 1997, 248, 31–40.
M. Kruszewski, Labile iron pool: The main determinant of cellular response to oxidative stress, Mut. Res., 2003, 29, 81–92.
B. P. Espósito, S. Epsztejn, W. Breuer, Z. I. Cabantchik, A review of fluorescence methods for assessing labile iron in cells and biological fluids, Anal. Biochem., 2002, 304, 1–18.
C. Hershko, G. Graham, G. W. Bates, E. A. Rachmilewitz, Non-specific serum iron in thalassaemia: an abnormal serum iron fraction of potential toxicity, Br. J. Haematol., 1978, 40, 255–263.
T. Ganz, E. Nemeth, Hepcidin and disorders of iron metabolism, Annu. Rev. Med., 2011, 62, 347–360.
E. Nemeth, M. S. Tuttle, J. Powelson, M. B. Vaughn, A. Donovan, D. M. Ward, T. Ganz, J. Kaplan, Hepcidin regulates cellular iron efflux by binding to ferroportin and inducing its internalization, Science, 2004, 306, 2090–2093.
B. A. Syed, P. J. Sargent, S. Farnaud, R. W. Evans, An overview of molecular aspects of iron metabolism, Hemoglobin, 2006, 30, 69–80.
L. Klautz, E. Nemeth, Novel tools for the evaluation of iron metabolism, Haematologica, 2010, 95, 1989–1991.
M. W. Hentze, L. C. Kuhn, Molecular control of vertebrate iron metabolism: mRNA-based regulatory circuits operated by iron, nitric oxide, and oxidative stress, Proc. Natl. Acad. Sci. U. S. A., 1996, 93, 8175–8182.
N. C. Andrews, Forging a field: the golden age of iron biology, Blood, 2008, 112, 219–230.
I. De Domenico, D. McVey Ward, J. Kaplan, Regulation of iron acquisition and storage: consequences for iron-linked disorders, Nat. Rev. Mol. Cell Biol., 2008, 9, 72–81.
Z. D. Liu, R. C. Hider, Design of clinically useful iron(III)-selective chelators., Med. Res. Rev., 2002, 22, 26–64.
B. Halliwell and J. M. C. Gutteridge, Free radicals, ageing, and disease, in Free Radicals in Biology and Medicine, second edition, Clarendon, Oxford, 1989, pp 416–493.
H. De Groot, Reactive oxygen species in tissue injury., Hepato-Gastroenterology, 1994, 41, 328–332.
S. J. Stohs, D. Bagchi, Oxidative mechanisms in the toxicity of metal ions, Free Radical Biol. Med., 1995, 18, 321–336.
M. Tenopoulo, P. T. Doulis, A. Barbouti, U. Brunk, D. Galaris, Role of compartmentalized redox active iron in hydrogen peroxide-induced DNA damage and apoptosis, Biochem. J., 2005, 387, 703–710.
C. Pourzand, O. Reelfs, R. M. Tyrrell, Approaches to define the involvement of reactive oxygen species and iron in ultraviolet-A inducible gene expression, Methods Mol. Biol., 2000, 99, 257–276.
G. Cairo, A. Pietrangelo, Iron regulatory proteins in pathobiology., Biochem. J., 2000, 352, 241–250.
B. G. Rosser, G. J. Gores, Liver cell necrosis: cellular mechanisms and clinical implications., Gastroenterology, 1995, 108, 252–275.
M. S. Sussman, G. B. Bulkley, Oxygen-derived free radicals in reperfusion injury, Methods Enzymol., 1990, 186, 711–722.
H. De Groot, M. Brecht, Reoxygenation injury in rat hepatocytes: mediation by O2-/H2O2 liberated by sources other than xanthine oxidase, Biol. Chem. Hoppe-Seyler, 1991, 372, 35–41.
L. Tacchini, S. Recalcati, A. Bernelli-Zazzera, G. Cairo, Induction of ferritin synthesis in ischemic-reperfused rat liver: analysis of the molecular mechanisms, Gastroenterology, 1997, 113, 946–953.
N. C. Andrews, Disorders of iron metabolism, N. Engl. J. Med., 1999, 341, 1986–1995.
A. Gaeta, R. C. Hider, The crucial role of metal ions in neurodegeneration: the basis for a promising therapeutic strategy, Br. J. Pharmacol., 2009, 146, 1041–1059.
S. Kalinowski, D. R. Richardson, The evolution of iron chelators for the treatment of iron overload disease and cancer, Pharmacol. Rev., 2005, 57, 547–583.
M. Molina-Holgado, R. C. Hider, A. Gaeta, R. Williams, P. Francis, Metals ions and neurodegeneration, BioMetals, 2007, 20, 639–654.
B. R. Bacon, R. S. Britton, The pathology of hepatic iron overload: a free radical-mediated process?, Hepatology, 1990, 11, 127–137.
J. P. Kehrer, The Haber-Weiss reaction and mechanisms of toxicity, Toxicology, 2000, 149, 43–50.
K. V. Kowdley, Iron, hemochromatosis, and hepatocellular carcinoma, Gastroenterology, 2004, 127, S79–S86.
M. Valko, C. J. Rhodes, J. Moncol, M. Izakovic, M. Mazur, Free radicals, metals and antioxidants in oxidative stress-induced cancer, Chem.-Biol. Interact., 2006, 160, 1–40.
M. Valko, D. Leibfritz, J. Moncol, M. T. D. Cronin, M. Mazur, Free radicals and antioxidants in normal physiological functions and human diseases, Int. J. Biochem. Cell Biol., 2007, 39, 44–84.
C. A. Swanson, Iron intake and regulation: implications for iron deficiency and iron overload, Alcohol, 2003, 30, 99–102.
G. J. Brewer, Risks of copper and iron toxicity during aging in humans, Chem. Res. Toxicol., 2010, 23, 319–326.
Y. Kongho, T. Ohtake, K. Ikuta, Y. Suzuki, Y. Hosoki, H. Saito, Iron accumulation in alcoholic liver diseases, Alcohol.: Clin. Exp. Res., 2005, 29, S189–S193.
D. R. Petersen, Alcohol, iron-associated oxidative stress, and cancer, Alcohol, 2005, 35, 243–249.
N. Imeryuz, V. Tahan, A. Sonsuz, F. Eren, S. Uraz, M Yuksel, Iron preloading aggravates nutritional steatohepatitis in rats by increasing apopotic cell death, J. Hepatol., 2007, 47, 851–859.
S. Toyokuni, Iron-induced carcinogenesis: the role of redox regulation, Free Radical Biol. Med., 1996, 20, 553–566.
D. R. Richardson, D. S. Kalinowski, S. Lau, P. J. Jansson, D. B. Lovejoy, Cancer cell iron metabolism and the development of potent iron chelators as anti-tumour agents, Biochim. Biophys. Acta, 2009, 1790, 702–717.
H. W. Hann, M. W. Stahlhut, B. S. Blumberg, Iron nutrition and tumor growth: decreased tumor growth in iron-deficient mice, Cancer Res., 1988, 48, 4168–4170.
L. Molin, P. O. Wester, Iron content in normal and psoriatic epidermis, Acta Derm. Venereol., 1973, 53, 473–476.
Z. Ackerman, M. Seidenbaum, E. Loewenthal, A. Rubinow, Overload of iron in the skin of patients with varicose ulcers. Possible contributing role of iron accumulation in progression of the disease, Arch. Dermatol., 1988, 124, 1376–1378.
T. J. David, F. E. Wells, T. C. Sharpe, A. C. Gibbs, J. Devlin, Serum levels of trace metals in children with atopic eczema, Br. J. Dermatol., 1990, 122, 485–489.
J. L. Sullivan, Iron and the sex difference in heart disease risk, Lancet, 1981, 317, 1293–1294.
J. Jian, E. Pelle, X. Huang, Iron and menopause: does increased iron affect the health of postmenopausal women?, Antioxid. Redox Signaling, 2009, 11, 2939–2943.
W. Y. Ong, B. Halliwell, Iron, atherosclerosis, and neurodegeneration: a key role for cholesterol in promoting iron-dependent oxidative damage?, Ann. N. Y. Acad. Sci., 2004, 1012, 51–64.
M. W. Hentze, T. A. Rouault, J. B. Harford, R. D. Klausner, Oxidation-reduction and the molecular mechanism of a regulatory RNA-protein interaction, Science, 1989, 244, 357–359.
E. W. Müllner, S. Rothenberger, A. M. Müller, L. C. Kühn, In vivo and in vitro modulation of the mRNA-binding activity of iron-regulatory factor. Tissue distribution and effects of cell proliferation, iron levels and redox state, Eur. J. Biochem., 1992, 208, 597–605.
E. A. Martins, R. L. Robalinho, R. Meneghini, Oxidative stress induces activation of a cytosolic protein responsible for control of iron uptake, Arch. Biochem. Biophys., 1995, 316, 128–134.
K. Pantopoulos, M. W. Hentze, Rapid responses to oxidative stress mediated by iron regulatory protein, EMBO J., 1995, 14, 2917–2924.
G. Cairo, E. Castrusini, G. Minotti, A. Bernelli-Zazzera, Superoxide and hydrogen peroxide-dependent inhibition of iron regulatory prtein activity: A protective stratagen against oxidative injury, FASEB J., 1996, 10, 1326–1335.
G. Cairo, L. Tacchini, G. Pogliaghi, E. Anzon, A. Tomasi, A. Bernelli-Zazzera, Induction of ferritin synthesis by oxidative stress. Transcriptional and post-transcriptional regulation by expansion of the ‘free’ iron pool, J. Biol. Chem., 1995, 270, 700–703.
A. Yiakouvaki, J. Savovic, A. Al-Qenaei, J. Dowden, C. Pourzand, Caged-Iron Chelators a novel approach towards protecting skin cells against UVA-induced necrotic cell death, J. Invest. Dermatol., 2006, 126, 2287–2295.
S. Basu-Modak, D. Ali, M. Gordon, T. Polte, A. Yiakouvaki, C. Pourzand, C. Rice-Evans, R. M. Tyrrell, Suppression of UVA-mediated release of labile iron by epicathecin-A link to lysosomal protection, Free Radical Biol. Med., 2006, 41, 1197–1204.
W. Breuer, M. Shvartsman, Z. I. Cabantchik, Intracellular labile iron, Int. J. Biochem. Cell Biol., 2008, 40, 350–354.
S. M. Keyse, R. M. Tyrrell, Heme oxygenase is the major 32 kDA stress protein induced in human skin fibroblasts by UVA radiation, hydrogen peroxide, and sodium arsenite., Proc. Natl. Acad. Sci. U. S. A., 1989, 86, 99–103.
C. Hanselmann, C. Mauch, S. Werner, Haem oxygenase-1: a novel player in cutaneous wound repair and psoriasis?, Biochem. J., 2001, 353, 459–466.
R. M. Tyrrell, in Heme-Oxygenase - The Elegant Orchestration of its Products in Medicine, ed. L. E. Otterbein and B. S. Zucherbraun, Nova, Science Publishers Inc, New York, 2005, pp. 333–350.
E. Kvam, V. Hejmadi, S. Ryter, C. Pourzand, R. M. Tyrrell, Heme oxygenase activity causes transient hypersensitivity to oxidative ultraviolet A radiation that depends on release of iron from heme, Free Radical Biol. Med., 2000, 28, 1191–1196.
G. F. Vile, R. M. Tyrrell, Oxidative stress resulting from ultraviolet A irradiation of human skin fibroblasts leads to a heme oxygenase-dependent increase in ferritin, J. Biol. Chem., 1993, 268, 14678–14681.
G. F. Vile, S. Basu-Modak, C. Waltner, R. M. Tyrrell, Heme-oxygenase 1 mediates an adaptive response to oxidative stress in human skin fibroblasts, Proc. Natl. Acad. Sci. U. S. A., 1994, 91, 2607–2610.
F. Lin, A. W. Girotti, Elevated ferritin production, iron containment, and oxidant resistance in hemin-treated leukemia cells, Biochem. Pharmacol., 1997, 14, 1361–1363.
V. E. Reeve, D. Domanski, Refractoriness of UVA-induced protection from photo-immunosuppression correlates with heme oxygenase response to repeated UVA exposure, Photochem. Photobiol., 2002, 76, 401–405.
W. K. McCourbey, M. D. Maines, The structure, organisation and differential expression of the gene encoding rat heme-oxygenase-2, Gene, 1994, 139, 155–161.
A. Noël, R. M. Tyrrell, Development of refractoriness of induced human heme oxygenase-1 gene expression to reinduction by UVA irradiation and hemin, Photochem. Photobiol., 1997, 66, 456–463.
S. Fakih, M. Podinovskaia, X. Kong, H. L. Collins, U. E. Schaible, R. C. Hider, Targeting the lysosome: Fluorescent iron (III) chelators to selectively monitor endosomal/lysosomal labile iron pools, J. Med. Chem., 2008, 51, 4539–4552.
M. Tenopoulou, T. Kurz, P. T. Doulias, D. Galaris, U. T. Brunk, Does the calcein-AM method assay the total cellular ‘labile iron pool’ or only a fraction of it?, Biochem. J., 2007, 403, 261–266.
Y. Ma, H. de Groot, Z. Liu, R. C. Hider, F. Petrat, Chelation and determination of labile iron in primary hepatocytes by pyridinone fluorescent probes, Biochem. J., 2006, 395, 49–55.
Y. Ma, W. Luo, P. J. Quinn, Z. Liu, R. C. Hider, Design, Synthesis, Physicochemical properties and evaluation of novel iron chelators with fluorescent sensors, J. Med. Chem., 2004, 47, 6349–6362.
F. Petrat, U U. Rauen, H. de Groot, Determination of the chelatable iron pool of isolated rat hepatocytes by digital fluorescence microscopy using the fluorescent probe, phen green SK, Hepatology, 1999, 29, 1171–1179.
F. Petrat, H. de Groot, U. Rauen, Determination of the chelatable iron pool of single intact cells by laser scanning microscopy, Arch. Biochem. Biophys., 2000, 376, 74–81.
F. Petrat, H. de Groot, U. Rauen, Subcellular distribution of chelatable iron: a laser scanning microscopic study in isolated hepatocytes and liver endothelial cells, Biochem. J., 2001, 356, 61–69.
F. Petrat, D. Weisheit, M. Lensen, H. de Groot, R. Sustmann, U. Rauen, Selective determination of mitochondrial chelatable iron in viable cells with a new fluorescent sensor, Biochem. J., 2002, 362, 137–147.
O. Reelfs, R. M. Tyrrell, C. Pourzand, Ultraviolet A radiation-induced immediate iron release is a key modulator of the activation of NF-kappaB in human skin fibroblasts, J. Invest. Dermatol., 2004, 122, 1440–1447.
M. Shvartsman, E. Fibach, Z. I. Cabantchik, Transferrin iron routing to the cytosol and mitochondria as studied by live and real-time fluorescence, Biochem. J., 2010, 429, 185–193.
W. Breuer, M. Shvartsman, Z. I. Cabantchik, Intracellular labile iron, Int. J. Biochem. Cell Biol., 2008, 40, 350–354.
Y. Yu, Z. Kovacevic, D. R. Richardson, Tuning cell cycle regulation with an iron key, Cell Cycle, 2007, 6, 1982–1994.
R. S. Ohgami, D. R. Campagna, E. L. Greer, B. Antiochos, A. McDonald, J. Chen, J. J. Sharp, Y. Fujiwara, J. E. Barker, M. D. Fleming, Identification of a ferrireductase required for efficient transferrin-dependent iron uptake in erythroid cells, Nat. Genet., 2005, 37, 1264–1269.
H. Gunshin, B. Mackenzie, U. V. Berger, Y. Gunshin, M. F. Romero, W. F. Boron, S. Nussberger, J. L. Gollan, M. A. Hediger, Cloning and characterization of a mammalian proton-coupled metal-ion transporter, Nature, 1997, 388, 482–488.
R. S. Eisenstein, Iron regulatory proteins and the molecular control of mammalian iron metabolism, Annu. Rev. Nutr., 2000, 20, 627–662.
P. Arosio, S. Levi, Cytosolic and mitochondrial ferritins in the regulation of cellular iron homeostasis and oxidative damage, Biochim. Biophys. Acta, 2010, 1800, 783–792.
Y. Yu, J. Wong, D. B. Lovejoy, D. S. Kalinowski, D. R. Richardson, Chelators at the cancer coalface: desferrioxamine to Triapine and beyond, Clin. Cancer Res., 2006, 12, 6876–6883.
D. Darshan, L. Vanoaica, L. Richman, F. Beerman, L. C. Kühn, Conditional deletion of ferritin H in mice induces loss of iron storage and liver damage, Hepatology, 2009, 50, 852–860.
S. Omiya, S. Hikoso, Y. Imanishi, A. Saito, O. Yamaguchi, T. Takeda, I. Mizote, T. Oka, M. Taneike, Y. Nakano, Y. Matsumura, K. Nishida, Y. Sawa, M. Hori, K. Otsu, Downregulation of ferritin heavy chain decreases labile iron pool, oxidative stress and cell death in cardiomyocytes, J. Mol. Cell. Cardiol., 2009, 46, 59–66.
H. Shi, K. Z. Bencze, T. L. Stemmler, C. C. Philpott, A cytosolic iron chaperone that delivers iron to ferritin, Science, 2008, 320, 1207–1210.
H. Lange, G. Kispal, R. Lill, Mechanism of iron transport to the site of heme synthesis inside yeast mitochondria, J. Biol. Chem., 1999, 274, 18989–18996.
L. M. Garrick, K. Gniecko, J. E. Hoke, A. al-Nakeeb, P. Ponka, M. D. Garrick, Ferric-salicylaldehyde isonicotinoyl hydrazone, a synthetic iron chelate, alleviates defective iron utilization by reticulocytes of the Belgrade rat, J. Cell. Physiol., 1991, 146, 460–465.
A. S. Zhang, A. D. Sheftel, P. Ponka, Intracellular kinetics of iron in reticulocytes: evidence for endosome involvement in iron targeting to mitochondria, Blood, 2005, 105, 368–375.
A. D. Sheftel, A. S. Zhang, C. Brown, O. S. Shirihai, P. Ponka, Direct intraorganellar transfer of iron from endosomes to mitochondria, Blood, 2007, 110, 125–132.
G. C. Shaw, J. J. Cope, I. Li, K. Corson, C. Hersey, G. E. Ackermann, B. Gwynn, A. J. Lambert, R. A. Wingert, D. Traver, N. S. Trede, B. A. Barut, Y. Zhou, E. Minet, A. Donovan, A. Brownlie, R. Balzan, M. J. Weiss, L. I. Peters, J. Kaplan, L. I. Zon, B. H. Paw, Mitoferrin is essential for erythroid iron assimilation, Nature, 2006, 440, 96–100.
W. Chen, H. A. Dailey, B. H. Paw, Ferrochelatase forms an oligomeric complex with mitoferrin-1 and Abcb10 for erythroid heme synthesis, Blood, 2010, 116, 628–630.
P. Ponka, Tissue-specific regulation of iron metabolism and heme synthesis: distinct control mechanisms in erythroid cells, Blood, 1997, 89, 1–25.
J. Borova, P. Ponka, J. Neuwirt, Study of intracellular iron distribution in rabbit reticulocytes with normal and inhibited heme synthesis, Biochim. Biophys. Acta, 1973, 320, 143–156.
P. Ponka, A. Wilczynska, H. M. Schulman, Iron utilization in rabbit reticulocytes: a study using succinylacetone as an inhibitor of heme synthesis, Biochim. Biophys. Acta, Mol. Cell Res., 1982, 720, 96–105.
D. R. Richardson, P. Ponka, D. Vyoral, Distribution of iron in reticulocytes after inhibition of heme synthesis with succinylacetone: examination of the intermediates involved in iron metabolism., Blood, 1996, 87, 3477–3488.
A. May, E. Fitzsimons, Sideroblastic anaemia, Bailliere’s Clin. Haematol., 1994, 7, 851–879.
M. L. Adams, I. Ostapiuk, J. A. Grasso, The effects of inhibition of heme synthesis on the intracellular localization of iron in rat reticulocytes, Biochim. Biophys. Acta, Mol. Cell Res., 1989, 1012, 243–253.
T. K. Rostovtseva, S. M. Bezrukov, ATP transport through a single mitochondrial channel, VDAC, studied by current fluctuation analysis, Biophys. J., 1998, 74, 2365–2373.
S. Levi, E. Rovida, The role of iron in mitochondria function, Biochim. Biophys. Acta, 2009, 1790, 629–636.
F. Y. Li, B. Leibiger, I. Leibiger, C. Larsson, Characerisation of a putative murine mitochondrial transporter homology of hMRS3/4, Mamm. Genome, 2002, 13, 20–23.
C. Pourzand, O. Reelfs, E. Kvam, R. M. Tyrrell, IRP can determine the effectiveness of d-aminolevulinic acid in inducing protoporphyrin IX (PPIX) in primary human skin fibroblasts, J. Invest. Dermatol., 1999, 112, 101–107.
A. T. McKie, P. Marciani, A. Relfs, K. Brennan, K. Wehr, D. Barrow, S. Miret, T. J. Bomford, T. J. Peters, F. Farzaneh, M. A. Hediger, M. W. Hentze, R. J. Simpson, A novel duodenal iron-regulated transporter, IREG1, implicated in the basolateral transfer of iron to the circulation, Mol. Cell, 2000, 5, 299–309.
R. Lill, Functions and biogenesis of iron sulfur proteins, Nature, 2009, 460, 831–888.
I. J. Schultz, C. Chen, B. H. Paw, I Hamza, Iron and porphyrin trafficking in heme biogenesis, J. Biol. Chem., 2010, 285, 26753–26759.
U. Rauen, A. Springer, D. Weisheit, F. Petrat, H. G. Korth, H. de Groot, R. Sustmann, Assessment of chelatable mitochondrial iron by using mitochondrion-selective fluorescent iron indicators with different iron-binding affinities, ChemBioChem, 2007, 8, 341–352.
B. Sturm, U. Bistrich, M. Schranzhofer, J. P. Sarsero, U. Rauen, B. Scheiber-Mojdehkar, H. de Groot, P. Ioannou, F. Petrat, Friedreich’s ataxia, no changes in mitochondrial labile iron in human lymphoblasts and fibroblasts: a decrease in antioxidative capacity?, J. Biol. Chem., 2005, 280, 6701–6708.
T. Kurz, A. Terman, B. Gustafsson, U. T. Brunk, Lysosomes and oxidative stress in aging and apoptosis, Biochim. Biophys. Acta, 2008, 1780, 1291–1303.
Z. Yu, H. L. Persson, J. W. Eaton, U. T. Brunk, Intralysosomal iron: a major determinant of oxidant-induced cell death, Free Radical Biol. Med., 2003, 34, 1243–1252.
K. Kislyov, J. J. Jennings Jr, Y. Rbaibi, C. T. Chu, Autophagy, mitochondria and cell death in lysosomal storage diseases, Autophagy, 2007, 3, 259–262.
C. Settembre, A. Fraldi, L. Jahreiss, C. Spampanato, C. Venturi, D. Medina, R. D. Pablo, C. Tacchetti, D. C. Rubinsztein, A. Ballabio, A block of autophagy in lysosomal storage disorders, Hum. Mol. Genet., 2007, 17, 119–129.
H. Glickstein, R. B. El, G. Link, W. Breuer, A. M. Konijn, C. Hershko, H. Nick, Z. I. Cabantchik, Action of chelators in iron-loaded cardiac cells: Accessibility to intracellular labile iron and functional consequences,, Blood, 2006, 108, 3195–3203.
W. Breuer, E. Greenberg, Z. I. Cabantchik, Newly delivered transferrin iron and oxidative cell injury, FEBS Lett., 1997, 403, 213–219.
P. Morliere, S. Salmon, M. Aubailly, A. Rister, R. Santus, Sensitization of skin fibroblasts to UVA by excess iron, Biochim. Biophys. Acta, 1997, 1334, 283–290.
A. M. Konijn, H. Glickstein, B. Vaisman, E. G. Meyron-Holtz, I. N. Slotki, Z. I. Cabantchik, The cellular labile iron pool and intracellular ferritin in K562 cells, Blood, 1999, 94, 2128–2134.
W. Breuer, S. Epsztejn, Z. I. Cabantchik, Dynamics of the cytosolic chelatable iron pool of K562 cells, FEBS Lett., 1996, 382, 304–308.
C. E. Thomas, S. D. Aust, Reductive release of iron from ferritin by cation free radicals of paraquat and other bipyridyls, J. Biol. Chem., 1986, 261, 13064–13070.
B. J. Bolann, R. J. Ulvik, On the ability of superoxide to release iron from ferritin, Eur. J. Biochem., 1990, 193, 899–904.
Y. Bando, K. Aki, Superoxide-mediated release of iron from feritin by some flavoenzymes, Biochem. Biophys. Res. Commun., 1990, 168, 389–395.
F. Funk, J. P. Lenders, R. R. Crichton, W. Schneider, Reductive mobilisation of ferritin iron, Eur. J. Biochem., 1985, 152, 167–172.
D. W. Reif, Ferritin as a source of iron for oxidative damage, Free Radical Biol. Med., 1992, 12, 417–427.
S. D. Aust, C. F. Chignell, T. M. Bray, B. Kalyanaraman, R. P. Mason, Free radicals in toxicology, Toxicol. Appl. Pharmacol., 1993, 120, 168–178.
M. Aubailly, R. Santus, S. Salmon, Ferrous iron release from ferritin by ultraviolet A radiation, Photochem. Photobiol., 1991, 54, 769–773.
P. I. Oteiza, C. G. Kleinman, M. Demasi, E. J. H. Bechara, 5-aminolevulinic acid induces iron release from ferritin, Arch. Biochem. Biophys., 1995, 316, 607–611.
B. Vaisman, E. Fibach, A. M. Konijn, Utilization of intracellular ferritin iron for hemoglobin synthesis in developing human erythroid precursors, Blood, 1997, 90, 831–838.
M. Horackova, P. Ponka, Z. Byczko, The antioxidant effects of a novel iron chelator salicaldehyde isonicotinoyl hydrazone in the prevention of H2O2 injury in adult cardiomyocytes, Cardiovasc. Res., 2000, 47, 529–536.
T. Simunek, C. Boer, R. A. Bouwman, R. Vasblom, A. M. Versteilen, M. Sterba, V. Gersl, R. Hrdina, P. Ponka, J. J. de Lange, W. J. Paulus, R. J. Musters, SIH, a novel lipophilic iron chelator, protects H9c2 cardiomyoblasts from oxidative stress-induced mitochondrial injury and cell death, J. Mol. Cell. Cardiol., 2005, 39, 345–354.
T. Kurz, A. Terman, U. T. Brunk, Autophagy, ageing and apoptosis: the role of oxidative stress and lysosomal iron, Arch. Biochem. Biophys., 2007, 462, 220–230.
T. Kurz, A. Leake, T. Von Zglinicki, U. T. Brunk, Relocalized redox active lysosomal iron is an important mediator of oxidative-stress-induced DNA damage, Biochem. J., 2004, 378, 1039–1045.
M. Zhao, F. Antunes, J. W. Eaton, U. T. Brunk, Lysosomal enzymes promote mitochondrial oxidant production, cytochrome c release and apoptosis, Eur. J. Biochem., 2003, 270, 3778–3786.
T. Kurz, B. Gustafsson, U. T. Brunk, Intralysosomal iron chelation protects against oxidative stress-induced cellular damage, FEBS J., 2006, 273, 3106–3117.
H. L. Persson, Z. Yu, O. Tirosh, J. W. Eaton, U. T. Brunk, Prevention of oxidant-induced cell death by lysosomotropic iron chelators, Free Radical Biol. Med., 2003, 34, 1295–1305.
A. Cozzi, B. Corsi, S. Levi, P. Santambrogio, A. Albertini, P. Arosio, Overexpression of wild type and mutated human ferritin H-chain in Hela cels: in vivo role of ferroxidase activity, J. Biol. Chem., 2000, 275, 25122–25129.
S. Epsztejn, H. Glickstein, V. Piccard, I. N. Slotki, W. Breuer, C. Beaumont, Z. I. Cabantchik, H-ferritin subunit Overexpression in erythroid cells reduces the oxidative stress response and induces multidrug resistance properties, Blood, 1999, 94, 3593–3603.
H. Glickstein, R. B. El, M. Shvartsman, Z. I. Cabantchik, Intracellular labile iron pools as direct targets of iron chelators: a fluorescence study of chelator action in living cells, Blood, 2005, 106, 3242–3250.
O. Kakhlon, W. Breuer, A. Munnich, Z. I. Cabantchik, Iron redistribution as a therapeutic strategy for treating diseases of localized iron accumulation, Can. J. Physiol. Pharmacol., 2010, 88, 187–196.
A. Wong, J. Yang, P. Cavadini, C. Gellera, B. Lonnerdal, F. Taroni, G. Cortopassi, The Friedreich’s ataxia mutation confers cellular sensitivity to oxidant stress which is rescued by chelators of iron and calcium and inhibitors of apoptosis, Hum. Mol. Genet., 1999, 8, 425–430.
H. Itoh, T. Shioda, T. Matsura, S. Koyama, T. Nakanishi, G. Kajiyama, T. Kawasaki, Iron ions induces mitochondrial DNA damage in HTC rat hepatoma cell culture- role of antioxidants in mitochondrial DNA protection from oxidative stresses, Arch. Biochem. Biophys., 1994, 313, 120–125.
C. K. Lim, D. S. Kalinowski, D. R. Richardson, Protection against hydrogen peroxide-mediated cytotoxicity in Friedreich’s ataxia fibroblasts using novel iron chelators of the 2-pyridylcarboxaldehyde isonicotinoyl hydrazone class, Mol. Pharmacol., 2008, 74, 225–235.
A. Uchiyama, J-S. Kim, K. Kon, H. Jaeschke, K. Ikejima, S. Watanabe, J. J. Lemasters, Translocation of iron from lysosome into mitochondria is a key event during oxidative stress-induced hepatocellular injury, Hepatology, 2008, 48, 1644–1654.
R. A. Swerlick, N. J. Korman, UVA and NF-kappaB activity: ironing out the details, Comment on: J. Invest. Dermatol. 2004 122:1440–1447, J. Invest. Dermatol., 2004, 122, xi–xii.
E. Kvam, R. M. Tyrrell, Induction of oxidative DNA base damage in human skin cells by UV and near visible radiation, Carcinogenesis, 1997, 18, 2379–2384.
S. Mecklenburg, C. A. Collins, M. Döring, T. Burkholz, M. Abbas, F. H. Fry, C. Pourzand, C. Jacob, The design of multifunctional antioxidants against the damaging ingredients of oxidative stress, Phosphorus, Sulfur Silicon Relat. Elem., 2008, 183, 863–888.
C. A. Collins, F. H. Fry, A. L. Holme, S. Pariagh, A. Yiakouvaki, A. Al-Qenaei, C. Pourzand, C. Jacob, Towards Multifunctional Antioxidants: Synthesis, Electrochemistry, in vitro and Cell Culture Evaluation of Compounds with Ligand/Catalytic Properties, Org. Biomol. Chem., 2005, 3, 1541–1546.
L. A. Applegate, A. Noel, G. Vile, E. Frenk, R. M. Tyrrell, Two genes contribute to different extents to the heme oxygenase enzyme activity measured in cultured human skin fibroblasts and keratinocytes: implications for protection against oxidant stress, Photochem. Photobiol., 1995, 61, 285–291.
M. J. Pygmalion, L. Ruiz, E. Popovic, J. Gizard, P. Portes, X. Marat, K. Lucet-Levannier, B. Muller, J. B. Galey, MJ Pygmalion, L Ruiz, E Popovic, J Gizard, P Portes, X Marat, K Lucet-Levannier, B Muller, JB Galey, Skin cell protection against UVA by Sideroxyl, a new antioxidant complementary to sunscreens, Free Radical Biol. Med., 2010, 49, 1629–1637.
M. Creighton-Gutteridge, R. M. Tyrrell, A novel iron chelator that does not induce HIF-1 activity, Free Radical Biol. Med., 2002, 33, 356–363.
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Aroun, A., Zhong, J.L., Tyrrell, R.M. et al. Iron, oxidative stress and the example of solar ultraviolet A radiation. Photochem Photobiol Sci 11, 118–134 (2012). https://doi.org/10.1039/c1pp05204g
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DOI: https://doi.org/10.1039/c1pp05204g