mitoquinone and Chemical-and-Drug-Induced-Liver-Injury

Mitochondrial oxidative stress has been a crucial mediator in acetaminophen (APAP)-induced hepatotoxicity. MitoQ, an analog of coenzyme Q10, is targeted towards mitochondria and acts as a potent antioxidant. This study aimed to explore the effect of MitoQ on APAP-induced liver injury and its possible mechanisms. To investigate this, CD-1 mice and AML-12 cells were treated with APAP. Hepatic MDA and 4-HNE, two markers of lipid peroxidation (LPO), were elevated as early as 2 h after APAP. Oxidized lipids were rapidly upregulated in APAP-exposed AML-12 cells. Hepatocyte death and mitochondrial ultrastructure alterations were observed in APAP-induced acute liver injury. The in vitro experiments showed that mitochondrial membrane potentials and OXPHOS subunits were downregulated in APAP-exposed hepatocytes. MtROS and oxidized lipids were elevated in APAP-exposed hepatocytes. We discovered that APAP-induced hepatocyte death and liver injury were ameliorated by attenuation of protein nitration and LPO in MitoQ-pretreated mice. Mechanistically, knockdown of GPX4, a key enzyme for LPO defense systems, exacerbated APAP-induced oxidized lipids, but did not influence the protective effect of MitoQ on APAP-induced LPO and hepatocyte death. Whereas knockdown of FSP1, another key enzyme for LPO defense systems, had little effect on APAP-induced lipid oxidation but partially weakened the protection of MitoQ on APAP-induced LPO and hepatocyte death. These results suggest that MitoQ may alleviate APAP-evoked hepatotoxicity by eliminating protein nitration and suppressing hepatic LPO. MitoQ prevents APAP-induced liver injury partially dependent of FSP1 and independent of GPX4.

Topics: Acetaminophen; Animals; Chemical and Drug Induced Liver Injury; Chemical and Drug Induced Liver Injury, Chronic; Hepatocytes; Leukemia, Myeloid, Acute; Liver; Mice; Mice, Inbred C57BL; Oxidative Stress

The mitochondria are the primary source of reactive oxygen species (ROS) under pathological condition, but the significance of mitochondrial ROS in the development of Lipopolysaccharide (LPS)/D-galactosamine (D-Gal)-induced acute liver injury remains unclear. In the present study, the level of mitochondrial ROS in LPS/D-Gal has been determined by MitoSox staining and the potential roles of mitochondrial ROS in LPS/D-Gal-induced liver injury have been investigated by using the mitochondria-targeting antioxidant MitoQ. The results indicated that LPS/D-Gal exposure induced the generation of mitochondrial ROS while treatment with MitoQ reduced the level of mitochondrial ROS. Treatment with MitoQ ameliorated LPS/D-Gal-induced histopathologic abnormalities, suppressed the elevation of AST and ALT, and increased the survival rate of the experimental animals. Treatment with MitoQ also suppressed LPS/D-Gal-induced production of tumor necrosis factor α (TNF-α), inhibited the activities of caspase-3, caspase-8 and caspase-9, decreased the level of cleaved caspase-3 and reduced the counts of TUNEL positive cells. These results indicate that mitochondrial ROS is involved in the development of LPS-induced acute liver injury and the mitochondria-targeting antioxidant MitoQ might have potential value for the treatment of inflammation-based acute liver injury.

Topics: Animals; Antioxidants; Chemical and Drug Induced Liver Injury; Galactosamine; Lipopolysaccharides; Male; Mice; Mice, Inbred BALB C; Mitochondria, Liver; Organophosphorus Compounds; Ubiquinone