The therapeutic effect of nicotinamide riboside chloride on ameliorating alcohol-induced neuronal damage with a focus on mitochondrial unfolded protein response and mitophagy

Excessive alcohol consumption leads to neurodegeneration, driven primarily by oxidative stress and mitochondrial dysfunction, yet no specific treatment exists. Nicotinamide riboside chloride (NRC), a nicotinamide adenine dinucleotide precursor, has demonstrated therapeutic potential in mitigating mitochondrial dysfunction in heart failure, but its role in alcohol-induced neurodegeneration remains unexplored. This study investigated NRC’s neuroprotective effects using behavioral tests, serum ethanol and inflammatory marker analysis, hematoxylin-eosin staining, and molecular assays of in vitro models. Proteomics and GEO database analysis further elucidated the mechanisms of alcohol-induced brain injury. Results showed that NRC significantly improved alcohol-related cognitive impairment and neuroinflammation. Both our experimental data and external datasets identified mitochondrial dysfunction as a key driver of alcohol-induced neuronal damage, characterized by impaired mitophagy and disrupted mitochondrial unfolded protein response (UPR^mt). NRC supplementation restored mitochondrial homeostasis by enhancing UPR^mt and Fundc1-dependent mitophagy. Mechanistically, UPR^mt inhibition abolished NRC’s protective effects by suppressing Fundc1 expression and mitophagy, whereas mitophagy inhibition did not affect UPR^mt, suggesting a hierarchical regulation where UPR^mt governs Fundc1-mediated mitophagy. In conclusion, alcohol disrupts mitochondrial quality control, but NRC counteracts neuronal toxicity by activating UPR^mt and restoring Fundc1-driven mitophagy, offering a promising therapeutic strategy for alcohol-related neuronal damage.