摘要
Ferroptosis is a newly described form of regulated cell death, distinct from apoptosis, necroptosis and other forms of cell death. Ferroptosis is induced by disruption of glutathione synthesis or inhibition of glutathione peroxidase 4, exacerbated by iron, and prevented by radical scavengers such as ferrostatin-1, liproxstatin-1, and endogenous vitamin E. Ferroptosis terminates with mitochondrial dysfunction and toxic lipid peroxidation. Although conclusive identification of ferroptosis in vivo is challenging, several salient and very well established features of neurodegenerative diseases are consistent with ferroptosis, including lipid peroxidation, mitochondrial disruption and iron dysregulation. Accordingly, interest in the role of ferroptosis in neurodegeneration is escalating and specific evidence is rapidly emerging. One aspect that has thus far received little attention is the antioxidant transcription factor nuclear factor erythroid 2-related factor 2 (Nrf2). This transcription factor regulates hundreds of genes, of which many are either directly or indirectly involved in modulating ferroptosis, including metabolism of glutathione, iron and lipids, and mitochondrial function. This potentially positions Nrf2 as a key deterministic component modulating the onset and outcomes of ferroptotic stress. The minimal direct evidence currently available is consistent with this and indicates that Nrf2 may be critical for protection against ferroptosis. In contrast, abundant evidence demonstrates that enhancing Nrf2 signaling is potently neuroprotective in models of neurodegeneration, although the exact mechanism by which this is achieved is unclear. Further studies are required to determine to extent to which the neuroprotective effects of Nrf2 activation involve the prevention of ferroptosis.
摘要译文
Ferroptosis是一种新描述的受调节细胞死亡形式，不同于细胞凋亡，坏死性凋亡和其他形式的细胞死亡。通过破坏谷胱甘肽合成或抑制谷胱甘肽过氧化物酶4诱导Ferroptosis，其被铁加剧，并且被自由基清除剂如ferrostatin-1，liproxstatin-1和内源性维生素E阻止。铁蛋白沉积症终止于线粒体功能障碍和毒性脂质过氧化。尽管在体内对结核病的确定性鉴定具有挑战性，但神经退行性疾病的一些显着且非常完善的特征与脂肪细胞增生症相一致，包括脂质过氧化，线粒体破坏和铁失调。因此，对于神经变性中的ferroptosis作用的兴趣正在升级，并且特定证据正在迅速出现。迄今为止很少受到关注的一个方面是抗氧化转录因子核因子红细胞2相关因子2（Nrf2）。该转录因子调节数百种基因，其中许多基因直接或间接参与调节细胞凋亡，包括谷胱甘肽，铁和脂质的代谢以及线粒体功能。这可能将Nrf2定位为调节ferroptotic应激的发作和结果的关键确定性成分。目前可获得的最小直接证据与此一致，并表明Nrf2可能对于防止腐殖起病是至关重要的。相比之下，大量证据表明增强Nrf2信号在神经变性模型中具有潜在的神经保护作用，尽管其实现的确切机制尚不清楚。需要进一步研究以确定Nrf2激活的神经保护作用涉及预防肺上垂的程度。
Moataz Abdalkader, Riikka Lampinen, Katja M. Kanninen, Tarja M. Malm, Jeffrey R. Liddell. Targeting Nrf2 to Suppress Ferroptosis and Mitochondrial Dysfunction in Neurodegeneration[J]. Frontiers in Neuroscience, 2018,12