ARMC10 (S43) phosphorylation mediates trimethyltin chloride-induced cognitive impairment through mitochondrial...

Trimethyltin chloride (TMT) is a well-established environmental neurotoxin known to induce hippocampal damage and cognitive impairment. Abnormal mitochondrial dynamics are involved in TMT-induced neurotoxicity, but the underlying molecular mechanisms remain unclear. Here, our study revealed that TMT-induced mitochondrial fragmentation led to mitochondrial dysfunction, nerve cell death and cognitive deficit. We assessed the expression of mitochondrial dynamics‑related proteins (OPA1, MFN1/2, DRP1, and FIS1). Using phosphoproteomics, we further identified Ser43 (S43) as a phosphorylation site in ARMC10, a protein implicated in mitochondrial dynamics. TMT exposure elevated the phosphorylation level of ARMC10^S43, validated by the anti-ARMC10^S43 phospho-specific antibody and parallel reaction monitoring (PRM). The overexpression of nonphosphorylatable ARMC10^S43A, but not phosphomimic ARMC10^S43D, remarkably antagonized TMT-induced mitochondrial fragmentation and dysfunction in vitro and in vivo. Immunoprecipitation-coupled mass spectrometry (IP-MS), followed by co-localization analysis and proximity ligation assay (PLA), verified that phosphorylated ARMC1^S43 targets MTFP1 and BNIP3, contributing to TMT-induced neurotoxicity. We identified the natural product derivative 1-(3,5-dimethylbenzenesulfonyl)-8',9'-dimethyl-5'H-spiro[piperidine-4,4'-pyrrolo[1,2-a]quinoxaline] from over 160,000 natural product-derived compounds library as a potential inhibitor of ARMC10 phosphorylation at S43, which antagonizes TMT-induced mitochondrial fragmentation and dysfunction. This study provides a better understanding of how post-translational modifications regulate mitochondrial dynamics in TMT-induced memory disorders, and offers guidance for a comprehensive assessment of the ecological and health risks associated with neurodegenerative diseases.