Neuroprotective effect of folic acid by maintaining DNA stability and mitochondrial homeostasis through the ATM/CHK2/P53/PGC-1α pathway in alcohol-exposed mice

Excessive drinking leads to alcoholic brain injury, which is characterized by neuroinflammation, cognitive decline and motor dysfunction. These pathological features are closely related to chromosomal DNA damage and mitochondrial dysfunction. In this study, we aimed to uncover the neuroprotective effects of folic acid (FA) in mice with alcoholic brain injury. C57BL/6J mice were used to establish the murine model of alcoholic brain injury after 12 weeks of alcohol exposure. FA treatment significantly increased the levels of ATP and mitochondrial DNA (mtDNA) copy number in brain tissues of alcohol-exposed mice, and regulated the imbalance of mitochondrial homeostasis in cortical nerve cells. Furthermore, it could reduce the leakage of mtDNA into the cytoplasm, thereby inhibiting the cGAS/STING/NLRP3 inflammatory pathway and alleviating neuroinflammation. In addition, FA treatment reduced DNA damage in peripheral blood lymphocytes and decreased the expression of 53BP1 and γ-H2AX proteins in brain tissues of alcohol-exposed mice. At the molecular level, FA reduced DNA damage by downregulating the ATM/CHK2/P53 pathway and induced the expression of peroxisome proliferator-activated receptor γ coactivator 1α (PGC-1α), which further inversely enhanced mitochondrial function through positive feedback. Collectively, this study provides experimental evidence that FA protects DNA stability and mitochondrial homeostasis in alcohol-exposed mice by downregulating the ATM/CHK2/P53/PGC-1α signaling pathway.