The role of mTORC1/TFEB axis mediated lysosomal biogenesis and autophagy impairment in fluoride neurotoxicity and the intervention effects of resveratrol

Elevated exposures to fluoride have been linked to neurological diseases. Identifying mechanisms of fluoride neurotoxicity and finding ways for prevention and treatment of epidemic fluorosis are important issues of public health. In this study, fluoride inhibited TFEB nuclear translocation by activating p-mTORC1/p-p70S6K, thus inhibiting lysosomal biogenesis, leading to dysfunctional lysosome accumulation, which further negatively affected autophagosome and lysosome fusion, thus impairing autophagy degradation, evidenced by the blocked conversion of LC3II to LC3I, and the increased p62 levels. Interestingly, RSV alleviated rats' cognition by improving fluoride-induced nerve damage and promoted lysosomal biogenesis demonstrated by the increased nucleus translocation of TFEB via inhibiting p-mTORC1 and p-p70S6K, the decreased expression of LC3II and p62. Collectively, we clarified the correlation between fluoride neurotoxicity and mTORC1/TFEB-mediated lysosomal biogenesis and autophagy. Meanwhile, RSV appeared to be a promising drug for the prevention and treatment of epidemic fluorosis.