L-BMAA induces neurotoxicity through AMPK/Akt-TSC1/2-mTOR-mediated mitophagy dysregulation and apoptosis.

Under the context of global climate change, the growing frequency of cyanobacterial blooms has heightened scientific focus on the neurotoxicity of β-N-methylamino-L-alanine (L-BMAA)-an environmental neurotoxin linked to neurodegeneration disorders. However, the precise cellular mechanisms underlying its neurotoxicity remain unclear. In this study, we aimed to elucidate these mechanisms using both in vitro (human SH-SY5Y neuroblastoma cells) and in vivo (zebrafish) models, and utilized transcriptomics, biochemical assays, and behavioral analyses. In vitro studies revealed that L-BMAA enhances oxidative stress, disrupts mitochondrial function, and triggers destructive mitophagy and apoptosis. Transcriptomic (RNA-seq) and proteomic (mass spectrometry) analyses identified apoptosis- and mitochondrial function-related pathways as central targets. Mechanistically, Western blots demonstrated that L-BMAA promotes mitophagy in SH-SY5Y cells by enhancing AMPK-TSC1/2-mTOR signaling while concurrently weakening the Akt-TSC1/2-mTOR axis, a pathway shift validated by specific inhibitor experiments. Consistent with these cellular mechanisms, in vivo results demonstrate that L-BMAA exposure impairs zebrafish learning, spatial memory, and induces anxiety-like behaviors. These behavioral deficits are linked to brain mitochondrial dysfunction and oxidative stress. Furthermore, transcriptomic analysis of zebrafish brain tissue confirmed significant dysregulation of genes involved in mitochondrial function. Overall, our study establishes that mitochondrial dysfunction and exaggerated mitophagy contribute to L-BMAA-induced injury in both zebrafish brains and SH-SY5Y cells, offering a potential therapeutic target for treating therapy-refractory neurodegenerative diseases caused by environmental factors.