Iron homeostasis is regulated by iron regulatory proteins, IRP1 and IRP2, which bind to iron responsive elements (IRE) in the mRNA of proteins of iron metabolism such as ferritin (iron storage). IRP2 undergoes iron-mediated degradation, and this pathway shares notable similarities with that of hypoxia-inducible factor 1 (HIF-1). It has been reported that oxidative stress marked by increased reactive oxygen species (ROS) signal HIF-1 stabilization in hypoxia. The role of ROS in IRP2 regulation is not well-established. We show that the degree of hypoxia induces differential effects on iron-mediated degradation of IRP2, such that IRP2 levels are 3-fold higher when exposed to 0.1% O 2 compared to 3% O2 after 4 hours of iron treatment. Hydrogen peroxide (H2O2) affects IRP2 by inducing IRE-binding activity after 12 hours, which is accompanied by decreased ferritin levels. Furthermore, the ability of H2O2 to protect IRP2 against iron-dependent degradation is similar to that of hypoxia. Finally, both intracellular and extracellular sources of oxidative stress protect IRP2 from ascorbate-mediated degradation. Taken together, these results support a role of ROS in protecting IRP2 against iron-mediated degradation and indicate that oxidative stress modulates downstream effects of IRP2.

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