Clusterin increases mitochondrial respiratory chain complex I activity and protects against hexavalent chromium-induced cytotoxicity in L-02 hepatocytes
Clusterin increases mitochondrial respiratory chain complex I activity and protects against hexavalent chromium-induced cytotoxicity in L-02 hepatocytes
复制标题
Clusterin 增加线粒体呼吸链复合物 i 活性并防止 L-02 肝细胞中六价铬诱导的细胞毒性
DOI：
10.1039/c8tx00231b
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发表时间：
2019-01-01
影响因子：
2.1
通讯作者：
Xiao, Fang
中科院分区：
文献类型：
--
作者：
Xiao, Yuanyuan;Zeng, Ming;Xiao, Fang
先前的证据表明，在水被六价铬[Cr(vi)]污染的地区，肝癌死亡率显着升高，这强调我们应该更加关注Cr(vi)诱导的肝细胞细胞毒性。我们发现 Clusterin (CLU) 在 Cr(vi) 暴露的 L-02 肝细胞中上调，但 CLU 在 Cr(vi) 诱导的细胞毒性中所起的作用从未被探索过。在本研究中，我们证明Cr（vi）靶向线粒体呼吸链复合物I（MRCC I）活性并诱导活性氧（ROS）积累，从而引起线粒体损伤，其特征是通透性转换孔（PTP）开放率增加，线粒体膜电位（MMP）崩溃，以及凋亡诱导因子（AIF）和细胞色素C（Cyt C）从线粒体释放到细胞质，然后诱导细胞活力丧失和天冬氨酸转氨酶增加(AST)/丙氨酸转氨酶 (ALT) 泄漏。我们发现Cr(vi)可能通过ROS-共济失调毛细血管扩张突变体(ATM)-胰岛素样生长因子1(IGF-1)轴调节CLU表达，并且CLU表达与MRCC I活性呈正相关。我们进一步证实CLU可能通过调节其亚基烟酰胺腺嘌呤二核苷酸脱氢酶（泛醌）Fe-S蛋白3（NDUFS3）的表达来调节MRCC I活性。通过建立CLU过表达细胞，我们发现CLU的过表达减轻了Cr(vi)诱导的MRCC I抑制，并进一步挽救了细胞活力丧失并减少了AST和ALT渗漏。因此，我们得出的结论是，CLU 诱导的 MRCC I 活性增加可以防止 Cr(vi) 诱导的细胞毒性。本研究将为彻底阐明Cr(vi)的细胞毒性和致癌机制提供新的实验证据。
Previous evidence revealed significant elevated liver cancer mortality in the areas where water was contaminated with hexavalent chromium [Cr(vi)], which highlighted that we should pay more attention to Cr(vi)-induced cytotoxicity in hepatocytes. We found that Clusterin (CLU) was up-regulated in Cr(vi)-exposed L-02 hepatocytes, but the role CLU played in Cr(vi)-induced cytotoxicity has never been explored. In the present study, we demonstrate Cr(vi) targeted mitochondrial respiratory chain complex I (MRCC I) activity and induced reactive oxygen species (ROS) accumulation, which caused mitochondrial damage that was characterized by the increase of permeability transition pore (PTP) open rate, the collapse of mitochondrial membrane potential (MMP), and the release of apoptosis-inducing factor (AIF) and Cytochrome C (Cyt C) from mitochondria to cytoplasm, which then induced cell viability loss and increased aspartate transaminase (AST)/alanine transaminase (ALT) leakage. We reveal that Cr(vi) may regulate CLU expression through the ROS-ataxia telangiectasia mutant (ATM)-insulin-like growth factor 1 (IGF-1) axis, and CLU expression was positively correlated to MRCC I activity. We further confirmed that CLU may regulate MRCC I activity via modulating its subunit nicotinamide adenine dinucleotide dehydrogenase (ubiquinone) Fe-S protein 3 (NDUFS3) expression. By the establishment of CLU over-expression cells, we found that over-expression of CLU alleviated Cr(vi)-induced MRCC I inhibition and further rescued cell viability loss and reduced AST and ALT leakage. Thus, we reached the conclusion that the CLU-induced increase of MRCC I activity protected against Cr(vi)-induced cytotoxicity. The present research will provide new experimental evidence for thoroughly clarifying the cytotoxicity and the carcinogenic mechanism of Cr(vi).