MtROS-Drp1-mediated mitochondria fission contributes to microglia BV2 cell apoptosis induced by titanium dioxide nanoparticles.

The widespread use of titanium dioxide nanoparticles (TiO2 NPs) has raised serious concerns regarding their biosafety, particularly their potential effects on the central nervous system. As innate immune cells in the brain, microglia serve as key targets for neurotoxicity assessment. This study aims to systematically elucidate the toxic effects of TiO2 NPs on BV2 cells and their underlying molecular mechanisms. The results showed that TiO2 NPs were spherical, with an average particle size of approximately 10 nm, and primarily existed in the anatase phase. TiO2 NPs significantly inhibited BV2 cell viability in a concentration-dependent manner and induced apoptosis as well as autophagosome formation. Mechanistically, TiO2 NPs exposure triggered mitochondrial network fragmentation, membrane depolarization, and bursts of both intracellular and mitochondrial ROS. Notably, the mitochondrial-targeted antioxidant mito-TEMPO effectively attenuated these deleterious effects. Western blot analysis further revealed that TiO2 NPs activated the mitochondria-dependent apoptotic pathway, upregulated the mitochondrial fission protein Drp1, downregulated the fusion protein OPA1, and promoted autophagic flux. Metabolomic analysis identified 206 significantly differentially expressed metabolites, primarily enriched in pathways such as the tricarboxylic acid cycle, glutamine metabolism, glutathione metabolism, and purine metabolism, revealing the metabolic basis of energy metabolism disruption and exacerbated oxidative stress. In summary, these findings demonstrate that TiO2 NPs induce oxidative stress, which drives mitochondrial dynamic imbalance (fission/fusion disruption) and dysfunction, subsequently triggering metabolic reprogramming, apoptosis, and autophagy in BV2 cells. This study provides important experimental evidence and novel mechanistic insights into the neurotoxic potential of TiO2 NPs.