Impaired Nuclear Nrf2 Translocation Undermines the Oxidative Stress Response in Friedreich Ataxia
Impaired Nuclear Nrf2 Translocation Undermines the Oxidative Stress Response in Friedreich Ataxia
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DOI：
10.1371/journal.pone.0004253
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发表时间：
2009-01-22
期刊：
影响因子：
3.7
通讯作者：
Rustin, Pierre
中科院分区：
文献类型：
--
作者：
Paupe, Vincent;Dassa, Emmanuel P.;Rustin, Pierre
背景：弗里德赖希共济失调起源于线粒体共济失调蛋白的减少，其导致一部分神经元的死亡。该疾病的生化标志包括低活性的铁硫簇含蛋白（ISP）和抗氧化防御机制，可能发挥重要作用，在疾病progress.Methodology/主要调查结果：因此，我们研究了参与抗氧化防御机制的信号通路。我们发现，培养的成纤维细胞与弗里德赖希共济失调患者表现出超敏反应的氧化损伤，因为在Nrf 2信号通路的损伤，这导致了错误的诱导抗氧化酶。这种损害起源于先前报道的肌动蛋白重塑过氧化氢.Conclusions/意义：因此，有缺陷的机械ISP合成引起线粒体铁代谢障碍增加过氧化氢的产生，占增加的易感性氧化应激。
Background: Friedreich ataxia originates from a decrease in mitochondrial frataxin, which causes the death of a subset of neurons. The biochemical hallmarks of the disease include low activity of the iron sulfur cluster-containing proteins (ISP) and impairment of antioxidant defense mechanisms that may play a major role in disease progression.Methodology/Principal Findings: We thus investigated signaling pathways involved in antioxidant defense mechanisms. We showed that cultured fibroblasts from patients with Friedreich ataxia exhibited hypersensitivity to oxidative insults because of an impairment in the Nrf2 signaling pathway, which led to faulty induction of antioxidant enzymes. This impairment originated from previously reported actin remodeling by hydrogen peroxide.Conclusions/Significance: Thus, the defective machinery for ISP synthesis by causing mitochondrial iron dysmetabolism increases hydrogen peroxide production that accounts for the increased susceptibility to oxidative stress.