Impaired Nuclear Nrf2 Translocation Undermines the Oxidative Stress Response in Friedreich Ataxia

Under basal conditions, the Nrf2-Keap1 complex, or a sub-pool of it attached to the mitochondrial outer membrane by the PGAM5 protein, is bound to the actin stress filament network of control cells. B. In frataxin-depleted cells, characterized by abnormal iron handling, the actin-Nrf2 signaling pathway is profoundly altered by the need to cope with elevated H2O2 levels. Removing H2O2 with the catalase mimetic Euk134 corrects these alterations. C. Treating control cells with oligomycin or tBHQ results in major oxidative stress that destabilizes the actin-Nrf2-Keap1 complex, leading to Nrf2 release and phosphorylation. Nuclear translocation of Nrf2 results in the recruitment of the co-activator(s) needed for Phase II antioxidant transcription. D. In frataxin-depleted cells, the oxidative insult induced by oligomycin (endogenous) or tBHQ (exogenous) cannot be counterbalanced by the induction of Phase II antioxidants, so that the cells are extremely sensitive to oxidation. Again, Euk134 treatment restores the actin-Nrf2 signaling pathway, allowing transcription of Phase II antioxidants.

Publication

Impaired Nuclear Nrf2 Translocation Undermines the Oxidative Stress Response in Friedreich Ataxia. (2009) Vincent Paupe, et al. PLoS One. 2009;4(1):e4253. Figure: F6. All organisms Mus musculus Homo sapiens Drosophila melanogaster Oryctolagus cuniculus Bos taurus Rattus norvegicus Capra hircus

Disease mentions