Iduna通过干扰聚（ADP-核糖）聚合酶-1诱导的细胞死亡（parthanatos）保护HT22细胞免受过氧化氢诱导的氧化应激。,Cellular Signalling

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Iduna通过干扰聚（ADP-核糖）聚合酶-1诱导的细胞死亡（parthanatos）保护HT22细胞免受过氧化氢诱导的氧化应激。
Cellular Signalling ( IF 4.4 ) Pub Date : 2013-01-22 , DOI: 10.1016/j.cellsig.2013.01.006
Haoxiang Xu ₁ , Peng Luo , Yongbo Zhao , Mingming Zhao , Yuefan Yang , Tao Chen , Kai Huo , Hua Han , Zhou Fei

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氧化应激诱导的细胞死亡在许多神经系统疾病中很常见。但是，尚未完全阐明聚（ADP-核糖）聚合酶-1诱导的细胞死亡（parthanatos）的作用。在这里，我们发现过氧化氢（H2O2）可能以浓度依赖的方式导致PARP-1激活和凋亡诱导因子核易位。Iduna，parthanatos的新型调节剂，也被H2O2诱导。基因消融对Iduna的下调促进了H2O2诱导的细胞损伤。Iduna的上调减少了线粒体电位的损失以及ATP和NAD +的产生，但并未影响线粒体功能障碍诱导的细胞色素c释放，Bax / Bcl-2比值的增加以及Caspase-9 / Caspase-3活性的增加。相反，Iduna的过表达抑制了PARP-1的活化和AIF的核易位。进一步的研究表明，PARP-1特异性抑制剂DPQ阻断了Iduna对H2O2诱导的氧化应激的保护作用。此外，在蛋白酶体抑制剂（MG-132）或泛素E1抑制剂（PYR-41）的存在下，Iduna的保护作用明显减弱。这些结果表明，Iduna通过改善线粒体功能和抑制氧化应激诱导的单性花蜜而起潜在的抗氧化剂作用，这些保护作用取决于泛素-蛋白酶体系统的参与。

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Iduna protects HT22 cells from hydrogen peroxide-induced oxidative stress through interfering poly(ADP-ribose) polymerase-1-induced cell death (parthanatos).

Oxidative stress-induced cell death is common in many neurological diseases. However, the role of poly(ADP-ribose) polymerase-1-induced cell death (parthanatos) has not been fully elucidated. Here, we found that hydrogen peroxide (H2O2) could lead to PARP-1 activation and apoptosis-inducing factor nuclear translocation in a concentration dependent manner. Iduna, as a novel regulator of parthanatos, was also induced by H2O2. Down-regulation of Iduna by genetic ablation promoted H2O2-induced cell damage. Up-regulation of Iduna reduced the loss of mitochondrial potential and ATP and NAD+ production, but did not affect the mitochondrial dysfunction-induced cytochrome c release, increase of Bax/Bcl-2 ratio, and Caspase-9/Caspase-3 activity. In contrast, overexpression of Iduna inhibited activation of PARP-1 and nuclear translocation of AIF. Further study showed that PARP-1 specific inhibitor, DPQ, blocked the protective effect of Iduna against H2O2-induced oxidative stress. Moreover, in the presence of proteasome inhibitor (MG-132) or ubiquitin E1 inhibitor (PYR-41), protective effect of Iduna was significantly weaken. These results indicate that Iduna acts as a potential antioxidant by improving mitochondrial function and inhibiting oxidative stress-induced parthanatos, and these protective effects are dependent on the involvement of ubiquitin-proteasome system.

更新日期：2013-01-15

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