‘Trojan-Horse’ stress-granule formation mediated by manganese oxide nanoparticles

Exposure to nanomaterials is considered as one of the risk factors for neurodegenerative pathology. <i>In vitro</i> 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 Mn₃O₄ NPs triggered SGs formation in cell-type-specific and metabolic-dependent manner. In human glioblastoma U87 MG cell line, Mn₃O₄ NPs entered cells within minutes and resided inside intracellular vesicles for at least 48 h. Mn₃O₄ NPs induced a strong reduction in oxidative phosphorylation rate, but not glycolysis. We showed that Mn₃O₄ NPs slowly dissolve producing a local net of Mn²⁺ cations, which are known to inhibit oxidative phosphorylation. Indeed, direct incubation of cells with equimolar amounts of Mn²⁺ cations triggered SGs formation and reduced cellular respiration rate. However, while SGs formed in response to Mn₃O₄ NPs persisted for hours, SGs formation by Mn²⁺ peaked and dropped within minutes. Finally, Mn₃O₄ NPs mediated SGs formation via the phosphorylation of eIF2α. Thus, we conclude that exposure of U87 MG cells to Mn₃O₄ NPs caused a ‘Trojan-horse’ prolonged SGs response.