Clusterin alleviates Cr(VI)-induced mitochondrial apoptosis in L02 hepatocytes via inhibition of Ca2+-ROS-Drpl-mitochondrial fission axis
Clusterin alleviates Cr(VI)-induced mitochondrial apoptosis in L02 hepatocytes via inhibition of Ca2+-ROS-Drpl-mitochondrial fission axis
复制标题
Clusterin 通过抑制 Ca(2 )-ROS-Drp1-线粒体裂变轴减轻 L02 肝细胞中 Cr(VI) 诱导的线粒体凋亡。
DOI：
10.1016/j.ecoenv.2020.111326
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发表时间：
2020-12-01
影响因子：
6.8
通讯作者：
Xiao, Fang
中科院分区：
文献类型：
--
作者：
Tang, Sixuan;Ye, Shuzi;Xiao, Fang
六价铬[Cr（VI）]在环境中普遍存在，通常用于各种工业过程。细胞外伴侣蛋白（chaperone protein，CLU）是一种具有抗凋亡功能的细胞外伴侣蛋白。在这项研究中，我们的目的是探讨CLU对铬（VI）诱导的线粒体分裂和凋亡的影响。结果表明，Cr（VI）处理的L02肝细胞凋亡率增加。CLU过表达对Cr（VI）诱导的肝细胞线粒体凋亡有保护作用。此外，Cr（VI）引发细胞内钙超载，导致黄嘌呤氧化酶（XO）的激活。Cr（VI）诱导活性氧（ROS）的过度产生，导致动力蛋白相关蛋白1（Drp 1）易位到线粒体，随后线粒体分裂，导致caspase-3依赖的线粒体凋亡，表现为线粒体通透性转换孔（mPTP）开放率增加，线粒体膜电位（MMP）降低，和更多的丙氨酸转氨酶（ALT）/天冬氨酸转氨酶（AST）渗漏到培养基中。而CLU过表达可激活AMPK通路，导致肌浆网Ca ~（2+）-ATP酶（SERCA 2a）表达增加。CLU诱导的AMPK/SERCA 2a活化减弱了钙超载、caspase-3活化和最终的线粒体凋亡。Cr（VI）通过Ca 2 +-ROS-Drp 1-线粒体分裂轴诱导肝细胞凋亡，CLU通过激活AMPK/SERCA 2a途径减轻线粒体凋亡。
Hexavalent chromium [Cr(VI)] is ubiquitous in the environment and is commonly used in various industrial processes. Clusterin (CLU) is an extracellular chaperone protein which exerts the anti-apoptotic function. In this study, we aimed to explore the effect of CLU on Cr(VI)-induced mitochondrial fission and apoptosis. We revealed that the apoptosis rate of L02 hepatocytes treated with Cr (VI) was increased. CLU over-expression could protect the hepatocytes from Cr(VI)-induced mitochondrial apoptosis. Furthermore, Cr(VI) triggered the intracellular calcium overload, resulting in the activation of xanthine oxidase (XO). Cr(VI) induced reactive oxygen species (ROS) overproduction, led to dynamin-related protein 1 (Drp1) translocation to mitochondria and the subsequent mitochondrial fission, contributing to the caspase-3-dependent mitochondrial apoptosis as evidenced by higher mitochondrial permeability transition pore (mPTP) opening rate, lower mitochondrial membrane potential (MMP), and more alanine transaminase (ALT)/aspartate transaminase (AST) leakage into the culture medium. However, CLU over-expression could trigger the AMP-activated protein kinase (AMPK) pathway, which was followed by the increase of sarcoplasmic reticulum Ca2+ -ATPase (SERCA2a) expression. CLU-induced AMPK/SERCA2a activation attenuated calcium overload, caspase-3 activation, and ultimate mitochondrial apoptosis. All in all, the present study demonstrated that Cr(VI) induced hepatocytes apoptosis via Ca2+-ROS-Drp1-mitochondria' fission axis and CLU alleviated the mitochondrial apoptosis through activation of the AMPK/SERCA2a pathway.