Exposure to copper induces mitochondria-mediated apoptosis by inhibiting mitophagy and the PINK1/parkin pathway in chicken (Gallus gallus) livers
Exposure to copper induces mitochondria-mediated apoptosis by inhibiting mitophagy and the PINK1/parkin pathway in chicken (Gallus gallus) livers
复制标题
暴露于铜可通过抑制鸡肝中的线粒体自噬和 PINK1/parkin 途径诱导线粒体介导的细胞凋亡
DOI：
10.1016/j.jhazmat.2020.124888
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发表时间：
2021
影响因子：
13.6
通讯作者：
Zhaoxin Tang
中科院分区：
文献类型：
--
作者：
Fan Yang;Jianzhao Liao;Wenlan Yu;Na Qiao;Jianying Guo;Qingyue Han;Ying Li;Lianmei Hu;Jiaqiang Pan;Zhaoxin Tang
铜 (Cu) 是一种具有重要细胞功能的过渡金属，过量存在时会引发氧化应激，从而产生毒性作用。然而，铜诱导的线粒体自噬和细胞凋亡之间的串扰及其潜在机制尚不清楚。在这里，我们在体内和体外探讨了铜诱导的线粒体自噬和细胞凋亡介导的肝毒性的机制。在体内实验中，给鸡饲喂不同浓度的铜（11、110、220和330 mg/kg）7周，导致肝组织超微结构损伤、线粒体自噬和细胞凋亡。原代鸡肝细胞的体外实验表明，铜处理24小时增加了线粒体自噬体的数量，并上调了PINK1、parkin和p62 mRNA水平以及parkin和p62 蛋白水平，诱导线粒体自噬。此外，用 3-甲基腺嘌呤 (3-MA) 处理会加剧 Cu 诱导的细胞周期 S 期停滞；增加细胞凋亡率； p53、Bak1、Bax、Cyt C 和 Caspase3/cleaved-caspase3 mRNA 和蛋白水平增加；并降低 Bcl2 mRNA 和蛋白水平。而雷帕霉素（Rapa）则对上述因素产生相反的作用。总的来说，结果表明，铜暴露可以通过鸡肝中的 PINK1/Parkin 通路引起线粒体自噬，并且线粒体自噬可能会减弱铜诱导的线粒体凋亡。
Copper (Cu), a transition metal with essential cellular functions, exerts toxic effects when present in excess by inducing oxidative stress. However, the Cu-induced crosstalk between mitophagy and apoptosis and the underlying mechanisms are unknown. Here, the mechanism of Cu-induced hepatotoxicity mediated by mitophagy and apoptosis was explored in vivo and in vitro. In in vivo experiments, chickens were fed a diet with various levels of Cu (11, 110, 220, and 330 mg/kg) for 7 weeks, which led to ultrastructural damage, mitophagy, and apoptosis in liver tissue.In vitroexperiments on primary chicken hepatocytes showed that Cu treatment for 24 h increased the numbers of mitophagosomes and upregulated PINK1, parkin, and p62 mRNA levels and parkin and p62 protein levels, inducing mitophagy. Moreover, treatment with 3- methyladenine (3-MA) aggravated Cu-induced S-phase arrest in cell cycle; increased the apoptotic rate; increased p53, Bak1, Bax, Cyt C, and Caspase3/cleaved-caspase3 mRNA and protein levels; and decreased Bcl2 mRNA and protein levels. However, rapamycin (Rapa) had the opposite effects on the above factors. In general, the results reveal that Cu exposure can cause mitophagy through the PINK1/Parkin pathway in chicken livers, and that mitophagy might attenuate Cu-induced mitochondrial apoptosis.