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 (H(2)O(2)) toxicity. Wild-type cortical cultures treated with 100-300microM H(2)O(2) 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 300microM H(2)O(2). Ferritin expression after H(2)O(2) 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.
Regan
Raymond F
RF
Department of Emergency Medicine, Thomas Jefferson University, 1020 Sansom Street, Thompson 239, Philadelphia, PA 19107, USA. Raymond.Regan@jefferson.edu
Li
Zhi
Z
Chen
Mai
M
Zhang
Xuefeng
X
Chen-Roetling
Jing
J
D000818:Animals; D002478:Cells, Cultured; D005293:Ferritins / Q000096:biosynthesis; D006861:Hydrogen Peroxide / Q000633:toxicity*; D035941:Iron Regulatory Protein 1 / Q000235:genetics / Q000502:physiology*; D035942:Iron Regulatory Protein 2 / Q000235:genetics / Q000502:physiology*; D051379:Mice; D018345:Mice, Knockout; D009474:Neurons / Q000166:cytology* / Q000187:drug effects* / Q000378:metabolism; D018384:Oxidative Stress / Q000235:genetics
D005293:Ferritins; D006861:Hydrogen Peroxide; D035941:Iron Regulatory Protein 1; D035942:Iron Regulatory Protein 2