The ROS Mediates MCUb in Mitochondria-Regulated Apoptosis of TM4 Cells Induced by Titanium Dioxide Nanoparticles

Titanium dioxide nanoparticles (TiO 2 NPs) can cause mitochondrial apoptosis of TM4 cells associated with reactive oxygen species (ROS) accumulation and Ca 2+ overload, but the relations among these processes remain unclear. This study aimed to evaluate whether the accumulation of ROS caused by TiO 2 NPs inhibits MCUb expression, leading to mitochondrial calcium overload and subsequent cell apoptosis through the mitochondrial pathway. TM4 cells were exposed to different concentrations of TiO 2 NPs (0, 25, 50, 75, 100?μg/mL) for 24?h. We assessed cell viability, ROS level, MCUb and VDAC1 expression, mitochondrial and cytoplasmic Ca 2+ levels, mitochondrial membrane potential (MMP), apoptosis rate, and key proteins related to mitochondrial apoptosis (Bcl-2, Bax, Caspase 3, Caspase 9, p53 and Cyt c). Additionally, the effect of N-acetylcysteine (NAC) on MCUb expression, calcium homeostasis, and cell apoptosis was evaluated. Compared to control group, TiO 2 NPs significantly increased ROS level, downregulated MCUb expression, elevated Ca 2+ levels in mitochondria and cytoplasm, and enhanced mitochondria-regulated apoptosis, starting from the 50?μg/mL TiO 2 NPs group. However, NAC significantly increased MCUb expression, attenuated Ca 2+ levels in mitochondria and cytoplasm, and reduced mitochondria-related apoptosis. In conclusion, TiO 2 NPs induced ROS accumulation, which inhibited the expression of MCUb. The decreased MCUb level led to Ca 2+ overload in mitochondria, causing TM4 cell apoptosis via the mitochondrial pathway. This research elucidates, for the first time, the role of MCUb and its relation with ROS in apoptosis of TM4 cells induced by TiO 2 NPs, which supplementing the molecular mechanism of cell apoptosis caused by TiO 2 NPs. Graphical Abstract

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