The role of Mfn2/PERK mediated ER-mitochondrial communication in autophagy induced by silica nanoparticles in HT22 cells.

Widespread application of silica nanoparticles (SiNPs) has raised concerns regarding potential neurotoxic risks, yet the complex mechanisms underlying cellular damage remain incompletely understood. Mitochondria associated endoplasmic reticulum membranes (MAMs), which are regulated by the key tethering protein Mitofusin 2 (Mfn2), serve as crucial platforms for interorgan crosstalk. However, whether ER-mitochondria communication mediated by Mfn2/PERK participate in SiNPs triggered neurotoxicity has not been elucidated. therefore, this study established an in vitro model of HT22 cells exposed to SiNPs to explore the mechanisms of the mitochondrial dynamic imbalance, ERS and autophagy. We detected cell viability, morphology and ultrastructure, antioxidant function, mtROS, Mfn2/PERK, mitochondrial dynamic, ERS, and autophagy-related proteins to investigate the role of mtROS/Mfn2/PERK in SiNPs-induced damage to HT22 cells. The results showed that the viability of HT22 cells was gradually decreased after exposure to 0-100μg/mL SiNPs for 24hours. Meanwhile, a series of cellular changes were observed, including oxidative damage, calcium overload, increased intracellular and mitochondrial ROS, decreased ATP content, broken mitochondrial cristae, swollen ER, expression of Mfn2 and PERK. Additionally, the structural and functional integrity of the Mfn2/PERK was impaired, and the expression of mitochondrial dynamics-related proteins was abnormal, thereby inducing ERS and promoting autophagy-related changes. Inhibition of mtROS or ERS and activation of Mfn2 alleviated mitochondrial dynamics imbalance and ERS, and were accompanied by attenuation of SiNPs-induced alterations in Mfn2/PERK signaling and autophagy-related proteins. This further confirms that there is a certain connection between mitochondrial function and ERS after SiNPs exposure, and that autophagy is induced through the mtROS/Mfn2/UPR signaling pathway.