Molecular mechanism underlying alcohol's residual effects: The role of acetaldehyde in mitochondrial dysfunction at synapses in mouse brain cortex

Abstract

Alcohol residual effects impose significant physiological and cognitive burdens due to acute ethanol exposure;however, its underlying mechanisms remain poorly understood. This study investigates the role of acetaldehyde,the main ethanol metabolite, in driving mitochondrial dysfunction and synaptic impairment during hangoveronset. Using a mice model, we evaluated the effects of ethanol (3.8 g/kg) and the alcohol dehydrogenase in-hibitor 4-methylpyrazole (4-MP) on brain cortex synaptosomes.Ethanol exposure significantly elevated serum acetaldehyde compared with control (p < 0.05), and inducedmitochondrial dysfunction, as evidenced by impaired respiration (30 % decrease in basal O2 uptake vs. control),mitochondrial membrane depolarization and reduced ATP production (50 % decrease vs. control). These effectswere mitigated by pre-treatment with 4-MP, which normalized acetaldehyde levels and partially restoredmitochondrial function. Notably, ethanol downregulated synaptic proteins (nNOS, GluN2B, PSD-95; p < 0.05),but 4-MP failed to prevent this reduction, suggesting that acetaldehyde would not be involved in synapticproteins alterations. Further, ethanol disrupted calcium homeostasis and nitric oxide (NO) content. Interestingly,4-MP alone also reduced calcium uptake and NO content (p < 0.05), indicating potential off-target effects onneuronal signaling.While the reduction in acetaldehyde levels preserved mitochondrial integrity, its inability to rescue synapticprotein loss highlights the complexity of hangover pathology, involving both acetaldehyde-dependent and -in-dependent mechanisms. Our findings underscore acetaldehyde’s pivotal role in hangover-associated mitochon-drial dysfunction but reveal divergent pathways in synaptic impairment. These insights advance the search fortargeted hangover therapies by delineating acetaldehyde-dependent toxicity.