SIRT3/AMPK-Driven Mitophagy Failure Underlies Methylmercury-Induced Neurotoxicity: Evidence from Humans to Cells.

Methylmercury (MeHg) is a global environmental pollutant notorious for its developmental neurotoxicity. Although many mechanisms of MeHg toxicity have been proposed, the precise molecular pathways remain incompletely understood. This study integrated population and cell models and utilized high-throughput transcriptomic screening of umbilical cord blood (UCB) and neuronal samples to identify differentially expressed genes associated with MeHg exposure. Subsequently, in vitro validation of the key mechanisms was performed. Omics data showed that differentially expressed genes in UCB from MeHg exposure are linked to mitophagy. Additionally, transcriptome sequencing of primary hippocampal neurons revealed the potential effects of MeHg on energy metabolism, indicating a mitochondrial mechanism that requires further investigation. Further in vitro mechanistic studies revealed that SIRT3/AMPK, key mediators of PINK1-dependent mitophagy, were activated by MeHg exposure. Notably, when PC12 cells were exposed to MeHg, SIRT3 was upregulated compensatorily. Our findings support a model in which MeHg-induced SIRT3 upregulation facilitates AMPKα (Thr172) phosphorylation via LKB1, suggesting that this pathway is associated with mitophagy activation, as evidenced by increased Beclin1 expression, LC3II/I conversion, and decreased p62 levels. Mitophagy was initiated as a defense response to remove damaged mitochondria and exogenous toxicants. Nevertheless, such successive cellular responses exacerbated mitochondrial stress, resulting in neuronal damage and synaptic underfeeding. Together, these results offer novel mechanistic insights into how SIRT3/AMPK-mediated mitophagy coordination regulates MeHg-induced neurotoxicity, providing potential therapeutic targets for developmental neurological disorders.