A New Effect of Aluminum on Iron Metabolism in Mammalian Cells

  • Satoru Oshiro
Part of the Structure and Bonding book series (STRUCTURE, volume 104)


There is an increasing number of reports about new effects of aluminum on iron metabolism in mammalian cells. In this review, based on our recent work and that by others, we describe how aluminum disturbs iron homeostasis. The effects of aluminum may help to explain the pathogenesis of neurodegeneration in Alzheimer’s disease.


Aluminum Iron Transferrin Iron regulatory protein Alzheimer’s disease 


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  1. 1.
    Basset P, Quesneau Y, Zwiller J (1986) Iron-induced L1210 cell growth: Evidence of a transferrin-independent iron transport. Cancer Res 46: 1644–1647Google Scholar
  2. 2.
    Inman RS, Wessling-Resnick M (1993) Characterization of transferrin-independent iron transport in K562 cells. J Biol Chem 268: 8521–8528Google Scholar
  3. 3.
    Kaplan J, Jordan I, Sturrock A (1991) Regulation of the transferrin-independent iron transport system in cultured cells. J Biol Chem 266: 2997–3004Google Scholar
  4. 4.
    Thorstensen K, Romslo I (1988) Uptake of iron from transferrin by isolated rat hepatocyte: A redox-mediated plasma membrane process. J Biol Chem 263: 8844–8850Google Scholar
  5. 5.
    Oshiro S, Nakajima H, Markello T, Krasnewich D, Bernardini I, Gahl WA (1993) Redox, transferrin-independent, and receptor-mediated endocytosis iron uptake system in cultured human fibroblasts. J Biol Chem 268: 21586–21591Google Scholar
  6. 6.
    Randell EW, Parkes JG, Olivieri NF, Templeton DM (1994) Uptake of non-transferrin-bound iron by both reductive and non-reductive processes is modulated by intracellular iron. J Biol Chem 269: 16046–16053Google Scholar
  7. 7.
    Sturrock A, Alexander J, Lamb J, Craven CM, Kaplan J (1990) Characterization of a transferrin-independent uptake system for iron in HeLa cells. J Biol Chem 265: 3139–3145Google Scholar
  8. 8.
    Benjamin L (1994) Genes V. Oxford University Press, New YorkGoogle Scholar
  9. 9.
    Gunshin H, Mackenzie B, Berger UV, Gunshin Y, Romero MF, Boron WF, Nussberger S, Gollan JL, Hediger A (1997) Cloning and characterization of a mammalian protoncoupled metal-ion transporter. Nature 388: 482–488CrossRefGoogle Scholar
  10. 10.
    Fleming MD, Romano MA, Su MA, Garrick LM, Garrick MD, Andrew NC (1998) Nramp2 is mutated in the anemic Belgrade (b) rat: Evidence of a role for Nramp2 in endosomal iron transport. Proc Natl Acad Sci USA 95: 1148–1153CrossRefGoogle Scholar
  11. 11.
    Ganrot PG (1986) Metabolism and possible health effects of aluminum. Environment Health Perspect 65: 363–441CrossRefGoogle Scholar
  12. 12.
    Roskams AJ, Connor JR (1990) Aluminum access to the brain: a role for transferrin and its receptor. Proc Natl Acad Sci USA 87: 9024–9027CrossRefGoogle Scholar
  13. 13.
    Oshiro S, Nakamura Y, Ishige R, Hori M, Nakajima H, Gahl, WA (1994) Reduction site of transferrin-dependent and transferrin-independent iron in cultured human fibroblasts. J Biochem 115: 849–852Google Scholar
  14. 14.
    Oshiro S, Kawahara M, Shirao M, Muramoto K, Kobayashi K, Ishige R, Nozawa K, Hori M, Cai Y, Kitajima S, Kuroda Y (1998) Aluminum taken up by transferrin-independent iron uptake affects the iron metabolism in rat cortical cells. J Biochem 123: 42–46Google Scholar
  15. 15.
    Oshiro S, Kawahara M, Kuroda Y, Zhang C, Cai Y, Kitajima S, Shirao M (2000) Glial cells contribute more to iron and aluminum accumulation but are more resistant to oxidative stress than neuronal cells. Biochim Biophys Acta 1502: 405–414Google Scholar
  16. 16.
    Takeda A, Devenyi A, Connor JR (1998) Evidence for non-transferrin-mediated uptake and release of iron and manganese in glial cell cultures from hypotransferrinemic mice. J Neurosci Res 51: 454–462CrossRefGoogle Scholar
  17. 17.
    Oshiro S, Nozawa K, Cai Y, Hori M, Kitajima S (1998) Characterization of a transferrin-independent iron uptake system in rat primary cultured cortical cells. J Med Dent Sci 45: 171–176Google Scholar
  18. 18.
    Abreo K, Abreo F, Sella ML, Jain S (1999) Aluminum enhances iron uptake and expression of neurofibrillary tangle protein in neuroblastoma cells. J Neurochem 72: 2059–2064CrossRefGoogle Scholar
  19. 19.
    Klausner RD, Rouaoult TA, Harford JB (1993) Regulating the fate of mRNA: the control of cellular iron metabolism. Cell 72: 19–28CrossRefGoogle Scholar
  20. 20.
    Theil EC (1994) Iron regulatory elements (IREs): a family of mRNA non-coding sequences. Biochem J 304: 1–11Google Scholar
  21. 21.
    Henze MW, Kuhn LC (1996) Molecular control of vertebrate iron metabolism: mRNA-based regulatory circuits operated by iron, nitric oxide, and oxidative stress. Proc Natl Acad Sci USA 93: 8175–8182CrossRefGoogle Scholar
  22. 22.
    Hail DJ, Rouaoult TA, Harford JB, Kennedy MC, Bondin GA, Beinert H, Klausner RD (1992) Cellular regulation of the iron-responsive element binding protein: disassembly of the cubane iron-sulfur cluster results in high-affinity RNA binding. Proc Natl Acad Sci USA 89: 11735–11739CrossRefGoogle Scholar
  23. 23.
    Hail DJ, Rouaoult TA, Tang CK, Chin J, Harford JB, Klausner RD (1992) Reciprocal control of RNA-binding and aconitase activity in the regulation of the iron-responsive element binding protein: role of the iron-sulfur cluster. Proc Natl Acad Sci USA 89: 7536–7540CrossRefGoogle Scholar
  24. 24.
    Oshiro S, Nozawa K, Hori M, Chun Zhang, Hashimoto Y, Kitajima S, Kawamura K (2002) Modulation of iron regulatory protein-1 by various metals. Biochem Biophys Res Comm 290: 213–218CrossRefGoogle Scholar
  25. 25.
    Guo B, Yu Y, Leibold EA (1994) Iron regulates cytoplasmic levels of a novel ironresponsive element-binding protein without aconitase activity. J Biol Chem 269: 24252–24260Google Scholar
  26. 26.
    Iwai K, Drake SK, Wehr NB, Weissman AM, LaVaute T, Minato N, Klausner RD, Levine RL, Rouault TA (1998) Iron-dependent oxidation, ubiquitination, and degradation of iron regulatory protein 2: implications for degradation of oxidized proteins. Proc Natl Acad Sci USA 95: 4924–4928CrossRefGoogle Scholar
  27. 27.
    Yamanaka K, Minato N, Iwai K (1999) Stabilization of iron regulatory protein 2, IRP2, by aluminum. FEBS Lett 462: 216–220CrossRefGoogle Scholar
  28. 28.
    Smith MA, Wehr K, Harris PLR, Siedlak SL, Connor JR, Perry G (1998) Abnormal localization of iron regulatory protein (IRP) in Alzheimer’s disease. Brain Res 788: 232–236CrossRefGoogle Scholar
  29. 29.
    Abreo K, Abreo F, Sella M, Jain S (1999) Aluminum enhances iron uptake and expression of neurofibirillary tangle protein in neuroblastoma cells. J Neurochem 72: 2059–2064CrossRefGoogle Scholar
  30. 30.
    Shin R-W, Lee VM-Y, Trojanowsky JQ (1994) Aluminum modifies the properties of AD PHFtau proteins in vivo and in vitro. J Neurosci 14: 7221–7233Google Scholar
  31. 31.
    Fleming J, Joshi JG (1987) Ferritin: isolation of aluminum-ferritin complex from brain. Proc Natl Acad Sci USA 84: 7866–7870CrossRefGoogle Scholar
  32. 32.
    Joshi JG, Fleming JT, Dhar M, Chauthaiwale VJ (1995) A novel ferritin heavy chain messenger ribonucleic acid in the human brain. J Neurol Sci 134: 52–56CrossRefGoogle Scholar
  33. 33.
    Clauberg M, Joshi JG (1993) Regulation of serine protease activity by aluminum: implications for Alzheimer disease. Proc Natl Acad Sci USA 90: 1009–1012CrossRefGoogle Scholar
  34. 34.
    Mantyh PW, Ghilardi JR, Rogers S, DeMaster E, Allen CJ, Stimson ER, Maggio JE (1993) Aluminum, iron, and zinc ions promote aggregation of physiological concentrations of beta-amyloid peptide. J Neurochem 61: 1171–1174CrossRefGoogle Scholar
  35. 35.
    Kawahara M, Muramoto K, Kobayashi K, Mori H, Kuroda Y (1994) Aluminum promotes the aggregation of Alzheimer’s amyloid beta-protein in vitro. Biochem Biophys Res Commun 198: 531–535CrossRefGoogle Scholar
  36. 36.
    Good PF, Perl DP, Bierer LM, Schmeidler J (1992) Selective accumulation of aluminum and iron in the neurofibrillary tangles of Alzheimer’s disease: a laser microprobe (LAMMA) study. Ann Neurol 31: 286–292CrossRefGoogle Scholar
  37. 37.
    Mashiko S, Suzuki N, Koga S, Nakano M, Goto T, Ashino T, Mizumoto I, Inaba H (1991) Measurement of rate constants for quenching singlet oxygen with a Cypridina luciferin analog (2-methyl-6-[p-methoxyphenyl]-3,7-dihydroimidazo [l,2-a]pyrazin-3-one) and sodium azide. J Biolumin Chemilumin 6: 69–72CrossRefGoogle Scholar
  38. 38.
    Koga S, Nakano M, Uehara K (1991) Mechanism for the generation of Superoxide anión and singlet oxygen during heme compound-catalyzed linoleic acid hydroperoxide decomposition. J Biolumin Chemilumin 289: 223–229Google Scholar
  39. 39.
    Siesjo BK (1984) Cerebral circulation and metabolism. J Neurosurg 60: 883–908Google Scholar
  40. 40.
    Makar TK, Nedergaad M, Preuss A, Gelbard AS, Perumal Cooper AJL (1994) Vitamin E, ascorbate, glutathione, glutathione disulfide, and enzymes of glutathione metabolism in cultures of chick astrocytes and neurons: Evidence that astrocytes play an important role in antioxidative processes in the brain. J Neurochem 62: 45–53CrossRefGoogle Scholar
  41. 41.
    Campbell A, Bondy SC (2000) Aluminum induced oxidative events and its relation to inflammation: a role for the metal in Alzheimer’s disease. Cell Mol Biol 46: 721–730Google Scholar
  42. 42.
    Bondy SC, Kirstein S (1996) The promotion of iron-induced generation of reactive oxygen species in nerve tissue by aluminum. Mol Chem Neuropathol 27: 185–194CrossRefGoogle Scholar
  43. 43.
    Lukiw WJ, Bazan NG (1998) Strong nuclear factor-kappaB-DNA binding parallels cyclooxygenase-2 gene transcription in aging and in sporadic Alzheimer’s disease superior temporal lobe neocortex. J Neurosci Res 153: 583–592CrossRefGoogle Scholar
  44. 44.
    Savory J, Rao JK, Huang Y, Letada PR, Herman MM (1999) Age-related hippocampal changes in Bcl-2: Bax ratio, oxidative stress, redoxactive iron and apoptosis associated with aluminum-induced neurodegeneration: increased susceptibility with aging. Neurotoxicology 20: 805–817Google Scholar
  45. 45.
    Guo GW, Liang YX (2001) Aluminum-induced apoptosis in cultured astrocytes and its effect on calcium homeostasis. Brain Res 888: 221–226CrossRefGoogle Scholar
  46. 46.
    Ghribi O, De Witt DA, Forbes MS, Herman MM, Savory J (2001) Co-involvement of mitochondria and endoplasmic reticulum in regulation of apoptosis: changes in cytochrome c, Bcl-2 and Bax in the hippocampus of aluminum-treated rabbits. Brain Res 903: 66–73CrossRefGoogle Scholar
  47. 47.
    Suarez-Fernandez MB, Soldado AB, Sanz-Medel A, Vega JA, Novelli A, Fernandez-Sanchez MT (1999) Aluminum-induced degeneration of astrocytes occurs via apoptosis and results in neuronal death. Brain Res 24: 835, 125-136Google Scholar
  48. 48.
    Goldbaum O, Richter-Landsberg C (2001) Stress proteins in oligodendrocytes: differential effects of heat shock and oxidative stress. J Neurochem 78: 1233–1234CrossRefGoogle Scholar
  49. 49.
    Poss KD, Tonegawa S (1997) Reduced stress defense in heme oxygenase 1-deficient cells. Proc Natl Acad Sci USA 94: 10925–10930CrossRefGoogle Scholar
  50. 50.
    Poss KD, Tonegawa S (1997) Heme oxygenase 1 is required for mammalian iron reutilization. Proc Natl Acad Sci USA 94: 10919–10924CrossRefGoogle Scholar
  51. 51.
    Oshiro S, Takeuchi H, Matsumoto M, Kurata S (1999) Transcriptional activation of heme oxygenase-1 gene in mouse spleen, liver and kidney cells after treatment with lipopolysaccharide or hemoglobin. Cell Biol Int 23: 465–474CrossRefGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 2002

Authors and Affiliations

  • Satoru Oshiro
    • 1
  1. 1.Biochemical Genetics, Medical Research InstituteTokyo Medical and Dental UniversityTokyoJapan

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