Mitochondrial dysfunction and oxidative stress are considered to be key events in acetaminophen (APAP)-induced acute liver injury. Mitochondrial quality control, including mitophagy and mitochondrial synthesis, can restore mitochondrial homeostasis and thus protect the liver. The role of PARK7, a mitochondrial stress protein, in regulating mitochondrial quality control in APAP-induced hepatotoxicity is unclear. In this study, L02 cells, AML12 cells and C57/BL6 mice were each used to establish models of APAP-induced acute liver injury. PARK7 was silenced in vitro by lentiviral transfection and knocked down in vivo by AAV adeno-associated virus. Changes in cell viability, apoptosis, reactive oxygen species (ROS) level, serum enzyme activity and pathological features were evaluated after APAP treatment. Western blotting, real-time PCR, immunofluorescence, electron microscopy and Seahorse assays were used to detect changes in key indicators of mitochondrial quality control. The results showed that APAP treatment decreased cell viability and increased the apoptosis rate, ROS levels, serum enzyme activity, pathological damage and PARK7 expression. PARK7 silencing or knockdown ameliorated APAP-induced damage to the cells and liver. Furthermore, PARK7 silencing enhanced mitophagy, increased mitochondrial synthesis, and led to a switch from oxidative phosphorylation to glycolysis. Taken together, these results suggest that PARK7 is involved in APAP-induced acute liver injury by regulating mitochondrial quality control and metabolic reprogramming. Therefore, PARK7 may be a promising therapeutic target for APAP-induced liver injury.
Keywords: APAP; PARK7; acute liver injury; mitochondrial quality control.