Illarionova Nina B, Morozova Ksenia N, Petrovskii Dmitry V, Sharapova Marina B, Romashchenko Alexander V, Troitskii Sergey Y, Kiseleva Elena, Moshkin Yuri M, Moshkin Mikhail P
Institute of Cytology and Genetics SB RAS, Novosibirsk, Russia.
Department of Natural Sciences, Novosibirsk State University, Novosibirsk, Russia.
Nanotoxicology. 2020 Dec;14(10):1432-1444. doi: 10.1080/17435390.2020.1856433. Epub 2020 Dec 15.
Exposure to nanomaterials is considered as one of the risk factors for neurodegenerative pathology. inorganic nanoparticles (NPs) absorb intrinsically disordered proteins, many of which are the constituents of stress-granules (SGs). SGs normally form in response to cellular stress and, here, we addressed whether selected inorganic NPs could trigger SGs formation in cells. To this end, we have tested a series of inorganic NPs for their ability to induce SGs formation in human glioblastoma and fibroblast cell lines. Among tested NPs, only MnO NPs triggered SGs formation in cell-type-specific and metabolic-dependent manner. In human glioblastoma U87 MG cell line, MnO NPs entered cells within minutes and resided inside intracellular vesicles for at least 48 h. MnO NPs induced a strong reduction in oxidative phosphorylation rate, but not glycolysis. We showed that MnO NPs slowly dissolve producing a local net of Mn cations, which are known to inhibit oxidative phosphorylation. Indeed, direct incubation of cells with equimolar amounts of Mn cations triggered SGs formation and reduced cellular respiration rate. However, while SGs formed in response to MnO NPs persisted for hours, SGs formation by Mn peaked and dropped within minutes. Finally, MnO NPs mediated SGs formation via the phosphorylation of eIF2α. Thus, we conclude that exposure of U87 MG cells to MnO NPs caused a 'Trojan-horse' prolonged SGs response.
接触纳米材料被认为是神经退行性病变的风险因素之一。无机纳米颗粒（NPs）会吸附内在无序蛋白，其中许多是应激颗粒（SGs）的组成成分。SGs通常在细胞应激时形成，在此我们探讨了选定的无机NPs是否能在细胞中触发SGs形成。为此，我们测试了一系列无机NPs在人胶质母细胞瘤和成纤维细胞系中诱导SGs形成的能力。在测试的NPs中，只有MnO NPs以细胞类型特异性和代谢依赖性方式触发SGs形成。在人胶质母细胞瘤U87 MG细胞系中，MnO NPs在数分钟内进入细胞，并在细胞内囊泡中停留至少48小时。MnO NPs导致氧化磷酸化速率大幅降低，但不影响糖酵解。我们发现MnO NPs缓慢溶解产生局部的Mn阳离子网络，已知这些阳离子会抑制氧化磷酸化。事实上，用等摩尔量的Mn阳离子直接孵育细胞会触发SGs形成并降低细胞呼吸速率。然而，虽然因MnO NPs形成的SGs会持续数小时，但由Mn触发的SGs形成在数分钟内达到峰值并下降。最后，MnO NPs通过eIF2α的磷酸化介导SGs形成。因此，我们得出结论，U87 MG细胞暴露于MnO NPs会导致一种“特洛伊木马”式的延长的SGs反应。
