Key Laboratory of Environmental Medicine Engineering of Ministry of Education, School of Public Health, Southeast University, Nanjing, Jiangsu, 210009, China.
Key Laboratory of Environmental Medicine Engineering of Ministry of Education, School of Public Health, Southeast University, Nanjing, Jiangsu, 210009, China.
Environ Pollut. 2020 Sep;264:114639. doi: 10.1016/j.envpol.2020.114639. Epub 2020 Apr 22.
Since ambient particulate matter (APM) is closely related to cardiovascular damage with mitochondria being its potential targets, this study was designed to explore the impact of APM on mitochondrial homeostasis, especially on mitochondrial dynamics and biogenesis in human vascular endothelial cells, using a kind of standard material, PM SRM1648a. As a result, internalized particles lead to mitochondrial dysfunction in EA.hy926 human endothelial cells, including mitochondrial reactive oxygen species (mtROS) overproduction, mitochondrial membrane potential (MMP) reduction and adenosine triphosphate (ATP) inhibition, coupled with additional release of mitochondrial DNA (mtDNA) into the cytosol. Moreover, morphological and structural changes in mitochondria are observed in response to PM SRM1648a. In that aspect, according to the evidence of shorter fragmented mitochondria dispersed throughout the cytoplasm, along with aberrant upregulation of fission-related mRNAs/proteins, the mitochondria exhibit a fission phenotype shifting from intact reticular network to fragmentized punctate shapes. Mechanistically, PM SRM1648a facilitates phosphorylation of DRP1 at Ser616 in HUVECs, and triggers its dephosphorylation at Ser637 residue in both EA.hy926 and HUVECs, which are supportive events for mitochondrial fission during particle exposure. Additionally, suppression of a master energy modulator, PGC-1α, reveals that PM SRM1648a has the ability to impair mitochondrial biogenesis. Collectively, it could be well concluded that PM SRM1648a interferes with the equilibrium of mitochondrial dynamics and biogenesis, which is likely to play a pivotal role in mitochondrial dysfunction driven by particles, eventually contributing to endothelial cell damage. Of note, it is more reasonable to conduct risk assessment from both cellular level and subcellular structures, among which mitochondria-targeted toxicity supplements more comprehensive understanding of APM inducible vascular toxicity.
由于环境细颗粒物（APM）与线粒体密切相关，线粒体是其潜在靶点，因此本研究旨在使用一种标准物质 PM SRM1648a 探索 APM 对人血管内皮细胞线粒体动态平衡的影响，特别是对线粒体动力学和生物发生的影响。结果表明，内化颗粒会导致 EA.hy926 人内皮细胞线粒体功能障碍，包括线粒体活性氧（mtROS）过度产生、线粒体膜电位（MMP）降低和三磷酸腺苷（ATP）抑制，同时伴随着线粒体 DNA（mtDNA）向细胞质的额外释放。此外，还观察到 PM SRM1648a 引起的线粒体形态和结构变化。在这方面，根据较短的碎片化线粒体分散在细胞质中的证据，以及分裂相关的 mRNA/蛋白质的异常上调，线粒体表现出从完整的网状网络到碎片化点状形状的分裂表型。从机制上讲，PM SRM1648a 促进了 HUVECs 中 DRP1 在 Ser616 位点的磷酸化，并触发了 EA.hy926 和 HUVECs 中 Ser637 残基的去磷酸化，这是颗粒暴露期间线粒体分裂的支持事件。此外，抑制主要的能量调节剂 PGC-1α 表明，PM SRM1648a 能够损害线粒体生物发生。总的来说，可以得出结论，PM SRM1648a 干扰了线粒体动力学和生物发生的平衡，这可能在颗粒驱动的线粒体功能障碍中发挥关键作用，最终导致内皮细胞损伤。值得注意的是，从细胞水平和亚细胞结构两个方面进行风险评估更为合理，其中靶向线粒体的毒性补充了对 APM 诱导的血管毒性的更全面的理解。
