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

• Published in: Biological & pharmaceutical bulletin 2023-04, Vol.46 (4), p.563-573, Article b22-00633
• Main Authors: Jin, Qian, Zhang, Yi, Cui, Yalan, Shi, Meng, Shi, Jingjing, Zhu, Siqing, Shi, Tong, Zhang, Ruihua, Chen, Xuejun, Zong, Xingxing, Wang, Chen, Li, Liqin
• Format: Article
• Language: English
• Subjects: Acetylcholinesterase; Acetylcholinesterase - metabolism; Animal models; Animals; Electron Transport; Electron transport chain; Energy metabolism; Enzyme-linked immunosorbent assay; Enzymes; Glutathione; Liver; Liver - metabolism; Male; Mitochondria; Oxidative stress; Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha - metabolism; Peroxisome proliferator-activated receptors; Protein turnover; Rats; Rats, Sprague-Dawley; Reactive oxygen species; Reactive Oxygen Species - metabolism; Soman; Soman - metabolism; Toxicity; Transcription Factors - metabolism; Transmission electron microscopy
• ISSN: 0918-6158; 1347-5215
• DOI: 10.1248/bpb.b22-00633

This work aimed to assess whether mitochondrial damage in the liver induced by subacute soman exposure is caused by peroxisome proliferator-activated receptor-gamma coactivator 1 alpha (PGC-1α) and whether PGC-1α 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 biochemically evaluated, and 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 quantitatively evaluated in isolated liver mitochondria by enzyme-linked immunosorbent assay (ELISA). PGC-1α 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 glutathione (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 compared with the control group, respectively. Among complexes I-IV, I-III decreased significantly (p