The AMPK-PGC-1α-SIRT3 axis mediates mitochondrial metabolic dysfunction and neuronal senescence induced by Al(mal)3 exposure in HT22 hippocampal neuronal cells.

Aluminum (Al) is a widely distributed environmental metal whose chronic exposure has been implicated in neurotoxicity and increased risk of neurodegenerative disorders. However, the molecular mechanisms linking aluminum exposure to neuronal metabolic dysfunction and senescence remain incompletely understood. In this study, mouse hippocampal neuronal HT22 cells were exposed to aluminum maltolate [Al (mal)3, 60-240 μM] to investigate alterations in mitochondrial bioenergetics and senescence-associated pathways. Aluminum exposure significantly increased senescence-associated β-galactosidase (SA-β-gal) activity and upregulated p16 and p21 expression, accompanied by G2/M phase arrest. Seahorse metabolic analysis revealed marked reductions in basal respiration, ATP-linked respiration, maximal respiratory capacity, glycolytic activity, and glycolytic reserve, indicating impaired mitochondrial function and metabolic flexibility. Mechanistically, aluminum exposure suppressed the AMPK-PGC-1α-SIRT3 signaling axis at both transcriptional and protein levels and reduced SOD2 and IDH2 enzymatic activities. Pharmacological activation of AMPK (AICAR) or SIRT3 (honokiol) partially restored mitochondrial respiration, glycolysis, antioxidant enzyme activity, and attenuated aluminum-induced neuronal senescence. Combined treatment also alleviated mitochondrial metabolic dysfunction and senescence-related alterations induced by aluminum exposure. Collectively, these findings suggest that disruption of the AMPK-PGC-1α-SIRT3 axis contributes to mitochondrial metabolic dysfunction and neuronal senescence under aluminum exposure. This study provides mechanistic insight into aluminum-induced neurotoxicity from a bioenergetic perspective and highlights mitochondrial metabolic regulation as a potential therapeutic target in environmental metal-associated neurological risk.