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Cadmium results in accumulation of autophagosomes-dependent apoptosis through activating Akt-impaired autophagic flux in neuronal cells.
Cellular Signalling ( IF 4.8 ) Pub Date : 2018-12-19 , DOI: 10.1016/j.cellsig.2018.12.008
Hai Zhang 1 , Xiaoqing Dong 1 , Rui Zhao 1 , Ruijie Zhang 1 , Chong Xu 1 , Xiaoxue Wang 1 , Chunxiao Liu 1 , Xiaoyu Hu 1 , Shile Huang 2 , Long Chen 1
Affiliation  

Environmental exposure to cadmium (Cd) links to neurodegenerative disorders. Autophagy plays an important role in controlling cell survival/death. However, how autophagy contributes to Cd's neurotoxicity remains enigmatic. Here, we show that Cd induced significant increases in autophagosomes with a concomitant elevation of LC3-II and p62 in PC12 cells and primary neurons. Using autophagy inhibitor 3-MA, we demonstrated that Cd-increased autophagosomes contributed to neuronal apoptosis. Impairment of Cd on autophagic flux was evidenced by co-localization of mCherry and GFP tandem-tagged LC3 puncta in the cells. This is further supported by the findings that administration of chloroquine (CQ) potentiated the basic and Cd-elevated LC3-II and p62 levels, autophagosome accumulation and cell apoptosis, whereas rapamycin relieved the effects in the cells in response to Cd. Subsequently, we noticed that Cd evoked the phosphorylation of Akt and BECN1. Silencing BECN1 and especially expression of mutant BECN1 (Ser295A) attenuated Cd-increased autophagosomes and cell death. Of note, inhibition of Akt with Akt inhibitor X, or ectopic expression of dominant negative Akt (dn-Akt), in the presence or absence of 3-MA, significantly alleviated Cd-triggered phosphorylation of Akt and BECN1, autophagosomes, and apoptosis. Importantly, we found that Cd activation of Akt functioned in impairing autophagic flux. Collectively, these results indicate that Cd results in accumulation of autophagosomes-dependent apoptosis through activating Akt-impaired autophagic flux in neuronal cells. Our findings underscore that inhibition of Akt to improve autophagic flux is a promising strategy against Cd-induced neurotoxicity and neurodegeneration.

中文翻译:

镉通过激活神经细胞中Akt受损的自噬通量,导致自噬体依赖性细胞凋亡的积累。

镉(Cd)暴露于环境会导致神经退行性疾病。自噬在控制细胞存活/死亡中起重要作用。然而,自噬如何导致Cd的神经毒性仍然是个谜。在这里,我们显示Cd诱导自噬体显着增加,并伴随PC12细胞和原代神经元中LC3-II和p62的升高。使用自噬抑制剂3-MA,我们证明镉增加的自噬小体有助于神经元凋亡。通过在细胞中mCherry和GFP串联标记的LC3点共同定位,可以证明Cd对自噬通量的损害。氯喹(CQ)的使用增强了碱性和镉升高的LC3-II和p62水平,自噬体积累和细胞凋亡,这一发现进一步证明了这一点。雷帕霉素可缓解细胞对Cd的影响。随后,我们注意到Cd诱发了Akt和BECN1的磷酸化。沉默BECN1,尤其是突变体BECN1(Ser295A)的表达可减轻Cd增加的自噬体和细胞死亡。值得注意的是,在存在或不存在3-MA的情况下,用Akt抑制剂X抑制Akt或异位表达显性阴性Akt(dn-Akt),可显着缓解Cd触发的Akt和BECN1磷酸化,自噬和凋亡。重要的是,我们发现Akt的Cd激活在损害自噬通量中起作用。总体而言,这些结果表明,Cd通过激活神经元细胞中Akt受损的自噬通量,导致自噬体依赖性细胞凋亡的积累。
更新日期:2018-12-19
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