Excessive alcohol consumption is a major contributor to cognitive impairment and neurodegenerative disorders, yet effective therapies that directly target alcohol-induced neuronal injury remain unavailable. Mounting evidence suggests that mitochondrial dysfunction plays a central role in alcohol-mediated brain damage, but the mechanisms responsible for mitochondrial failure are not fully understood.
A new study published in
Genes & Diseases by researchers from Chongqing Medical University and The First Medical Centre of Chinese PLA General Hospital, demonstrates that nicotinamide riboside chloride (NRC), a precursor of nicotinamide adenine dinucleotide (NAD⁺), protects neurons from alcohol-induced injury by restoring mitochondrial quality control through coordinated activation of the mitochondrial unfolded protein response (UPRmt) and mitophagy.
By utilizing
in vivo mouse models subjected to alcohol liquid feeding alongside
in vitro HT-22 neuronal cells, the researchers systematically evaluated cognitive behaviors and underlying mitochondrial dynamics. The behavioral and molecular data conclusively revealed that excessive alcohol exposure significantly exacerbates cognitive impairments, evident through increased escape latency and a notably thinned hippocampal dentate gyrus (DG) zone.
Crucially, the study uncovered that alcohol forces destructive mitochondrial fragmentation, evidenced by an increased number of abnormally small, fragmented mitochondria and a severe accumulation of reactive oxygen species (ROS). Comprehensive proteomic analyses of HT-22 cells further deciphered the complex intracellular networks, revealing that this toxic pathology is deeply intertwined with massive apoptosis and suppressed cell viability.
To directly counter these severe neurodegenerative effects, the researchers explored the therapeutic potential of NRC supplementation. Remarkably,
in vivo and
in vitro evaluations confirmed that the administration of NRC successfully reversed the aggravated pathology, fundamentally mitigating alcohol-induced cognitive impairments and suppressing the widespread inflammatory and apoptotic responses, including sharp reductions in the expression of Bax and Caspase-9. At the cellular level, NRC treatment completely reversed the structural damage, forcefully promoting mitochondrial elongation, restoring a healthy rod-shaped morphology, and rescuing both ATP production and mitochondrial membrane potential. Extensive molecular assays deciphered the exact signaling cascade, proving that NRC exerts its powerful neuroprotection primarily by enhancing Fundc1-dependent mitophagy.
Furthermore, NRC strongly modulated the unfolded protein response (UPR) by upregulating essential mitochondrial stress-response genes, specifically
Atf5 and
Lonp1, to actively restore overall mitochondrial integrity. While these comprehensive data robustly highlight the critical influence of tightly regulated mitochondrial quality control in protecting neuronal networks from alcohol toxicity, additional clinical studies are necessary to translate these specific protective pathways into human applications.
In conclusion, elucidating the significant neuroprotective role of NRC offers a powerful new strategy to combat alcohol-induced brain damage. This substantial finding directly positions targeted metabolic modulation, specifically through nicotinamide riboside chloride intervention, as a highly compelling therapeutic candidate for the next generation of treatments targeting substance-induced cognitive decline and neurodegeneration.
Reference
Title of Original Paper: The therapeutic effect of nicotinamide riboside chloride on ameliorating alcohol-induced neuronal damage with a focus on mitochondrial unfolded protein response and mitophagy
Journal: Genes & Diseases
Genes & Diseases is a journal for molecular and translational medicine. The journal primarily focuses on publishing investigations on the molecular bases and experimental therapeutics of human diseases. Publication formats include full length research article, review article, short communication, correspondence, perspectives, commentary, views on news, and research watch.
DOI: https://doi.org/10.1016/j.gendis.2025.101886
Funding Information:
Chongqing Graduate Student Research Innovation Project (No. CYB23192, Chongqing, China)
Independent Innovation Scientific Project of Chinese PLA General Hospital (No. 22QNCZ058, Beijing, China)
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