Disturbed mitochondrial quality control involved in hepatocytotoxicity induced by silica nanoparticles
Disturbed mitochondrial quality control involved in hepatocytotoxicity induced by silica nanoparticles
复制标题
二氧化硅纳米颗粒诱导的肝细胞毒性中线粒体质量控制的紊乱
DOI：
10.1039/d0nr01893g
复制
发表时间：
2020-06-28
期刊：
影响因子：
6.7
通讯作者：
Sun, Zhiwei
中科院分区：
文献类型：
--
作者：
Qi, Yi;Ma, Ru;Sun, Zhiwei
二氧化硅纳米粒子（SiNPs）的广泛应用不可避免地导致人类在职业、环境甚至医疗过程中暴露于其中。肝脏富含线粒体，是SiNPs的靶器官之一，但这些纳米粒子（NPs）与肝脏线粒体相互作用并影响其功能的潜在机制仍不清楚。在本研究中，我们检测了硅纳米粒子（SiNP）诱导的线粒体功能障碍，并进一步揭示了其对人肝细胞系L - 02中线粒体质量控制（MQC）的负面影响，包括线粒体动力学、线粒体自噬和生物发生。结果表明，SiNPs诱导细胞损伤，并伴有线粒体功能障碍，包括线粒体活性氧产生和线粒体膜电位崩溃。与透射电子显微镜（TEM）观察到的线粒体形态和长度分布异常一致，暴露于SiNPs的细胞线粒体呈现出分裂表型，检测到动力相关蛋白1（DRP1）和线粒体分裂蛋白1（FIS1）上调，而线粒体融合蛋白1（MFN1）下调。此外，暴露于SiNPs的细胞中微管相关蛋白1轻链3 - II（LC3II）水平升高、线粒体与溶酶体共定位、PTEN诱导的假定激酶1（PINK1）/帕金森病蛋白（Parkin）信号通路激活以及p62蛋白积累，表明SiNPs引发了线粒体自噬紊乱。此外，SiNPs抑制线粒体生物发生，这表现为线粒体质量和线粒体DNA拷贝数减少，以及过氧化物酶体增殖物激活受体γ共激活因子1α（PGC1α） - 核呼吸因子1（NRF1） - 线粒体转录因子A（TFAM）信号通路受到抑制。总体而言，该研究表明SiNPs通过干扰MQC过程引发肝细胞毒性，导致线粒体过度分裂、线粒体自噬紊乱以及线粒体生物发生受抑制，从而引起线粒体功能障碍和随之而来的细胞损伤，并最终促使肝脏疾病的发生和发展。我们的研究可为SiNPs的安全性评估提供重要的实验证据，特别是在生物医学应用领域。
The extensive application of silica nanoparticles (SiNPs) brings about inevitable occupational, environmental, and even iatrogenic exposure for human beings. The liver, which is rich in mitochondria, is one of the target organs of SiNPs, but the underlying mechanisms by which these nanoparticles (NPs) interact with liver mitochondria and affect their functions still remain unclear. In the present study, we examined silicon nanoparticle (SiNP)-induced mitochondrial dysfunction, and further revealed its negative effects on mitochondrial quality control (MQC) in the human liver cell line L-02, including mitochondrial dynamics, mitophagy and biogenesis. Consequently, SiNPs induced cellular injury, accompanied by mitochondrial dysfunction, including mitochondrial reactive oxygen generation and mitochondrial membrane potential collapse. In line with the transmission electron microscopy (TEM)-observed abnormalities in the mitochondrial morphology and length distribution, a fission phenotype was manifested in the mitochondria of SiNP-exposed cells, and up-regulated DRP1 and FIS1, and down-regulated MFN1, were detected. Furthermore, the enhanced LC3II level, colocalization of the mitochondria and lysosomes, activated PINK1/Parkin signaling, and accumulated p62 in the SiNP-exposed cells suggested mitophagy disorder triggered by SiNPs. In addition, SiNPs inhibited mito-biogenesis, as evidenced by the reduced mitochondrial mass and mtDNA copy number, as well as the suppressed PGC1 alpha-NRF1-TFAM signaling pathway. Overall, the study demonstrates that SiNPs trigger hepatocytotoxicity through interfering with the MQC process, bringing in excessive mitochondrial fission, mitophagy disorder and suppressed mito-biogenesis, leading to mitochondrial dysfunction and ensuing cell damage, and ultimately contributing to the occurrence and development of liver diseases. Our research could provide important experimental evidence related to safety assessments of SiNPs, especially in the field of biomedical applications.