Iduna protects HT22cells by inhibiting parthanatos: The role of the p53-MDM2 pathway.
Iduna protects HT22cells by inhibiting parthanatos: The role of the p53-MDM2 pathway.
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Iduna 通过抑制 parthanatos 保护 HT22 细胞：p53-MDM2 通路的作用
DOI：
10.1016/j.yexcr.2019.111547
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发表时间：
2019
影响因子：
3.7
通讯作者：
Luo Erping
中科院分区：
文献类型：
--
作者：
Xu Haoxiang;Li Xin;Wu Xiuquan;Yang Yuefan;Dai Shuhui;Lei Tao;Jing Da;Luo Peng;Luo Erping
目前，创伤性脑损伤（TBI）是一种常见且致命的疾病。聚二磷酸腺苷核糖聚合酶（PARP）诱导的细胞死亡（parthanatos）在TBI中的作用尚未得到很好的研究。我们过去的研究通过证实PARP活化和凋亡诱导因子（AIF）核易位的发生，表明氧化应激诱导的细胞死亡包括parthanatos。由于氧化应激在TBI后的病理进展中起着关键作用，我们认为Iduna的表达也可能减轻TBI， Iduna是唯一已知的parthanatos内源性调节因子。因此，本研究建立了HT-22 细胞的横断模型。下调Iduna可加重机械性细胞损伤引起的细胞损伤，上调Iduna可减轻机械性细胞损伤引起的线粒体功能障碍，但对线粒体功能障碍相关的凋亡无影响。相比之下，Iduna通过降低PARP的激活和AIF的核易位来预防parthanatos。我们还研究了2种新的p53-MDM2通路抑制剂AMG 232和Nutlin-3，它们大大降低了Iduna的保护作用。这些发现表明，Iduna可能通过特异性抑制parthanatos和促进线粒体功能来预防TBI，其中p53-MDM2通路发挥了关键作用。
Traumatic brain injury (TBI) is common and often fatal in current times. The role of poly(adenosine diphosphate-ribose) polymerase (PARP)-induced cell death (parthanatos) in TBI has not been well studied. Our past study showed that oxidative stress-induced cell death includes parthanatos by confirming the occurrence of PARP activation and nuclear translocation of apoptosis-inducing factor (AIF). As oxidative stress plays a key role in pathological progression after TBI, we believe TBI may also be alleviated by the expression of Iduna, which is the only known endogenous regulator of parthanatos. Thus, a transection model in HT-22 cells was established for present study. Downregulation of Iduna aggravated the cell damage caused by mechanical cell injury, whereas upregulation of Iduna reduced mitochondrial dysfunction induced by mechanical cell injury but exerted no effect on apoptosis associated with mitochondrial dysfunction. By contrast, Iduna prevented parthanatos by reducing PARP activation and nuclear translocation of AIF. We also investigated 2 novel p53-MDM2 pathway inhibitors, AMG 232 and Nutlin-3, which substantially reduced the protective effects of Iduna. These findings indicate that Iduna might prevent TBI by specifically inhibiting parthanatos and promoting mitochondrial function, with the p53-MDM2 pathway playing a critical role.