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Biometals

, Volume 16, Issue 1, pp 83–90 | Cite as

Iron-activated iron uptake: A positive feedback loop mediated by iron regulatory protein 1

  • Marto T. Núñez
  • Claudia Núñez-Millacura
  • Victoria Tapia
  • Patricia Muñoz
  • Dora Mazariegos
  • Miguel Arredondo
  • Pablo Muñoz
  • Casilda Mura
  • Ricardo B. Maccioni
Article

Abstract

The love-hate relationship between iron and living matter has generated mechanisms to maintain iron concentration in a narrow range, above and below which deleterious effects occur. At the cellular level, iron homeostasis is accomplished by the activity of the IRP proteins, which, under conditions of iron depletion, up-regulate the expression of the iron acquisition proteins TfR and DMT1. It has been shown that hydrogen peroxide activates IRP1 and that this activation mediates a potentially harmful increase in cell iron uptake. Here we show that IRP1 activity is also induced by iron-mediated oxidative stress. When cells were incubated with up to 20 μM of iron, a typical decrease in IRP1 and IRP2 activity was observed. Interestingly, when iron was further increased to 40 or 80 μM, IRP1 was reactivated in three of the four different cell lines tested, i.e., Caco-2 cells, N2A cells and HepG2 cells. In the fourth cell line (K562) IRP1 activity did not increase, but neither did it decrease. This response to iron was largely abrogated when the antioxidant N-acetyl cysteine was added along with iron to the culture medium. Thus, the effect of iron was mediated by oxidative stress. Increases in IRP1 activity were accompanied by increases in cell iron uptake, an indication that the activated IRP1 was functional in the activation of iron uptake. Hence, this iron-induced iron uptake feedback loop results in the increase of intracellular iron and increased oxidative stress.

apoptosis iron IRP oxidative stress 

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Copyright information

© Kluwer Academic Publishers 2003

Authors and Affiliations

  • Marto T. Núñez
    • 1
    • 2
  • Claudia Núñez-Millacura
    • 1
  • Victoria Tapia
    • 1
  • Patricia Muñoz
    • 1
  • Dora Mazariegos
    • 1
  • Miguel Arredondo
    • 1
  • Pablo Muñoz
    • 1
  • Casilda Mura
    • 1
  • Ricardo B. Maccioni
    • 1
  1. 1.Department of Biology, Faculty of SciencesUniversity of ChileSantiagoChile, and
  2. 2.Millennium Institute for Advanced Studies in Cell Biology and BiotechnologySantiagoChile

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