TY - JOUR

T1 - ‘Trojan-Horse’ stress-granule formation mediated by manganese oxide nanoparticles

AU - Illarionova, Nina B.

AU - Morozova, Ksenia N.

AU - Petrovskii, Dmitry V.

AU - Sharapova, Marina B.

AU - Romashchenko, Alexander V.

AU - Troitskii, Sergey Y.

AU - Kiseleva, Elena

AU - Moshkin, Yuri M.

AU - Moshkin, Mikhail P.

N1 - Publisher Copyright: © 2020 Informa UK Limited, trading as Taylor & Francis Group. Copyright: Copyright 2021 Elsevier B.V., All rights reserved.

PY - 2020/12

Y1 - 2020/12

N2 - Exposure to nanomaterials is considered as one of the risk factors for neurodegenerative pathology. In vitro 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.

AB - Exposure to nanomaterials is considered as one of the risk factors for neurodegenerative pathology. In vitro 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.

KW - manganese oxide

KW - Nanoparticles

KW - oxidative phosphorylation

KW - stress-granules

KW - Trojan-Horse mechanism

KW - RNA GRANULES

KW - OXIDATIVE STRESS

KW - MITOCHONDRIA

KW - TOXICITY

KW - IRON

KW - CELLULAR UPTAKE

KW - CYTOTOXICITY

KW - MN2+

UR - http://www.scopus.com/inward/record.url?scp=85097567432&partnerID=8YFLogxK

U2 - 10.1080/17435390.2020.1856433

DO - 10.1080/17435390.2020.1856433

M3 - Article

C2 - 33320703

AN - SCOPUS:85097567432

VL - 14

SP - 1432

EP - 1444

JO - Nanotoxicology

JF - Nanotoxicology

SN - 1743-5390

IS - 10

ER -