PGC 1? -Mediates Mitochondrial Damage in the Liver by Inhibiting the Mitochondrial Respiratory Chain as a Non-cholinergic Mechanism of Repeated Low-Level Soman Exposure

This work aimed to assess whether mitochondrial damage in the liver induced by subacute soman ex-posure is caused by peroxisome proliferator-activated receptor-gamma coactivator 1 alpha (PGC-1a) , whether PGC-1a regulates mitochondrial respiratory chain damage. Toxicity mechanism research may provide theoretical support for developing anti-toxic drugs in the future. First, a soman animal model was established in male Sprague-Dawley (SD) rats by subcutaneous soman injection. Then, liver damage was bio-chemically evaluated , acetylcholinesterase (AChE) activity was also determined. Transmission electron microscopy (TEM) was performed to examine liver mitochondrial damage, and high-resolution respirometry was carried out for assessing mitochondrial respiration function. In addition, complex I-IV levels were quan-titatively evaluated in isolated liver mitochondria by enzyme-linked immunosorbent assay (ELISA). PGC-1a levels were detected with a Jess capillary-based immunoassay device. Finally, oxidative stress was analyzed by quantifying superoxide dismutase (SOD), malondialdehyde (MDA), glutathione (GSH), oxidized gluta-thione (GSSG), and reactive oxygen species (ROS) levels. Repeated low-level soman exposure did not alter AChE activity, while increasing morphological damage of liver mitochondria and liver enzyme levels in rat homogenates. Complex I, II and I + II activities were 2.33, 4.95, and 5.22 times lower after treatment com-pared with the control group, respectively. Among complexes I-IV, I-III decreased significantly (p < 0.05), and PGC-1a levels were 1.82 times lower after soman exposure than in the control group. Subacute soman exposure significantly increased mitochondrial ROS production, which may cause oxidate stress. These find-ings indicated dysregulated mitochondrial energy metabolism involves PGC-1a protein expression imbal-ance, revealing non-cholinergic mechanisms for soman toxicity.