Role of the AMPK/PGC-1α/SIRT3-Mediated Mitochondrial Dysfunction in the Neurotoxicity of Methanol

Methanol (MeOH) is a volatile and flammable liquid commonly used in the construction, automotive, and pharmaceutical industries. It has systemic and ocular toxicity, and most patients with methanol poisoning have severe metabolic acidosis. Occupational inhalation can cause toxic optic neuropathy and bilateral optic atrophy. In this study, we investigated whether the 5'-AMP-activated protein kinase/peroxisome proliferator-activated receptor gamma coactivator 1-alpha/sirtuin-3 (AMPK/PGC-1α/SIRT3) pathway is involved in the methanol-induced mitochondrial dysfunction. A series of behavioral, histological, and pathological assessments was performed. Methanol exposure slowed down the weight growth rate of rats and prolonged escape latencies. In addition, methanol exposure decreased the number of upright times and horizontal movements, damaged cortical neurons, and caused oxidative stress injury. These alterations coincided with neurobehavioral impairments, indicating that methanol exposure may cause oxidative damage and mitochondrial dysfunction by down-regulating the expression levels of the AMPK/PGC-1α/SIRT3 pathway proteins. Treatment with ZLN005, a PGC-1α activator, partially alleviated methanol-induced neurobehavioral deficits and mitochondrial dysfunction, likely via the modulation of the AMPK/PGC-1α/SIRT3 pathway, which may be a novel target for therapeutics aimed to alleviate the effects of environmental neurotoxicants.