Department of Occupational Health and Environmental Health, School of Public Health, Capital Medical University, Beijing 100069, China; Beijing Key Laboratory of Environmental Toxicology, Capital Medical University, Beijing 100069, China.
Beijing Key Laboratory of Environmental Toxicology, Capital Medical University, Beijing 100069, China; Department of Toxicology and Sanitary Chemistry, School of Public Health, Capital Medical University, Beijing 100069, China.
Environ Pollut. 2018 May;236:926-936. doi: 10.1016/j.envpol.2017.10.060. Epub 2017 Nov 1.
As silica nanoparticles (SiNPs) pervade the global economy, however, the followed emissions during the manufacturing, use, and disposal stages inevitably bring an environmental release, potentially result in harmful impacts. Endothelial dysfunction precedes cardiovascular disease, and is often accompanied by mitochondrial impairment and dysfunction. We had reported endothelial dysfunction induced by SiNPs, however, the related mechanisms by which SiNPs interact with mitochondria are not well understood. In the present study, we examined SiNPs-induced mitochondrial dysfunction, and further demonstrated their adverse effects on mitochondrial dynamics and biogenesis in endothelial cells (HUVECs). Consequently, SiNPs entered mitochondria, caused mitochondrial swelling, cristae disruption and even disappearance. Further analyses revealed SiNPs increased the intracellular level of mitochondrial reactive oxygen species, eventually resulting in the collapse of mitochondrial membrane potential, impairments in ATP synthesis, cellular respiration and the activities of three ATP-dependent enzymes (including Na/K-ATPase, Ca-ATPase and Ca/Mg-ATPase), as well as an elevated intracellular calcium level. Furthermore, mitochondria in SiNPs-treated HUVECs displayed a fission phenotype. Accordingly, dysregulation of the key gene expressions (FIS1, DRP1, OPA1, Mfn1 and Mfn2) involved in fission/fusion event further certified the SiNPs-induced perturbation of mitochondrial dynamics. Meanwhile, SiNPs-treated HUVECs displayed declined levels of mitochondrial DNA copy number, PGC-1α, NRF1 and also TFAM, indicating an inhibition of mitochondrial biogenesis triggered by SiNPs via PGC-1α-NRF1-TFAM signaling. Overall, SiNPs triggered endothelial toxicity through mitochondria as target, including the induction of mitochondrial dysfunction, as well as the perturbations of their dynamics and biogenesis.
然而，随着硅纳米颗粒（SiNPs）在全球经济中的广泛应用，其在制造、使用和处置阶段产生的排放物不可避免地会释放到环境中，从而可能产生有害影响。内皮功能障碍先于心血管疾病发生，通常伴随着线粒体损伤和功能障碍。我们之前报道了 SiNPs 诱导的内皮功能障碍，但 SiNPs 与线粒体相互作用的相关机制尚不清楚。在本研究中，我们研究了 SiNPs 诱导的线粒体功能障碍，并进一步证明了它们对内皮细胞（HUVECs）中线粒体动力学和生物发生的不良影响。结果表明，SiNPs 进入线粒体，导致线粒体肿胀、嵴断裂甚至消失。进一步的分析表明，SiNPs 增加了线粒体活性氧的细胞内水平，最终导致线粒体膜电位崩溃、ATP 合成、细胞呼吸和三种 ATP 依赖性酶（包括 Na/K-ATP 酶、Ca-ATP 酶和 Ca/Mg-ATP 酶）的活性受损，以及细胞内钙离子水平升高。此外，SiNPs 处理的 HUVECs 中的线粒体呈现出裂变表型。因此，参与裂变/融合事件的关键基因表达（FIS1、DRP1、OPA1、Mfn1 和 Mfn2）的失调进一步证明了 SiNPs 诱导的线粒体动力学失调。同时，SiNPs 处理的 HUVECs 中线粒体 DNA 拷贝数、PGC-1α、NRF1 和 TFAM 的水平下降，表明 SiNPs 通过 PGC-1α-NRF1-TFAM 信号通路抑制了线粒体生物发生。总之，SiNPs 通过作为靶点的线粒体引发了内皮毒性，包括线粒体功能障碍的诱导，以及它们的动力学和生物发生的扰动。
Zotero 插件