Iron regulatory proteins increase neuronal vulnerability to hydrogen peroxide

Iron regulatory protein (IRP)-1 and IRP2 inhibit ferritin synthesis by binding to an iron responsive element in the 5′-untranslated region of its mRNA. The present study tested the hypothesis that neurons lacking these proteins would be resistant to hydrogen peroxide (H2O2) toxicity. Wild-type cortical cultures treated with 100-300 μM H2O2 sustained widespread neuronal death, as measured by lactate dehydrogenase assay, and a significant increase in malondialdehyde. Both endpoints were reduced by over 85% in IRP2 knockout cultures. IRP1 gene deletion had a weaker and variable effect, with approximately 20% reduction in cell death at 300 μM H2O2. Ferritin expression after H2O2 treatment was increased 1.9- and 6.7-fold in IRP1 and IRP2 knockout cultures, respectively, compared with wild-type. These results suggest that iron regulatory proteins, particularly IRP2, increase neuronal vulnerability to oxidative injury. Therapies targeting IRP2 binding to ferritin mRNA may attenuate neuronal loss due to oxidative stress.