Abstract
Mitochondrial dysfunction has been documented to play a crucial role in the pathogenesis of liver injury. In the present study, we investigated the role of rotenone, a mitochondrial complex-1 inhibitor, in carbon tetrachloride (CCl4) -induced acute liver injury, as well as the underlying mechanisms. Before CCl4 administration, the mice were pretreated with rotenone at a dose of 250 ppm in food for three days. Then CCl4 was administered to the mice for 16 h by intraperitoneal injection. The liver injury, mitochondrial status, oxidative stress, and inflammation were examined. Strikingly, CCl4 treatment markedly induced liver injury as shown by enhanced serum aspartate aminotransferase (AST) and alanine aminotransferase (ALT) and morphological lesions (HE stating), which was significantly attenuated by rotenone treatment in line with the reduced activity of mitochondrial complex-1. Meanwhile, oxidative stress markers of malondialdehyde (MDA), 4-hydroxynonenal (HNE), and dihydroethidium (DHE) and the inflammatory markers of IL-1β, MCP-1, TNF-α, TLR-4, and IL-6 were also significantly suppressed by rotenone. More importantly, the mitochondrial abnormalities shown by the reduction of SOD2, mitochondrial transcription factor A (TFAM), mitochondrial NADH dehydrogenase subunit 1 (mtND1), and Cytb were significantly restored, indicating that rotenone protected against mitochondrial damage induced by CCl4 in liver. Moreover, rotenone treatment alone did not significantly alter liver morphology and liver enzymes ALT and AST. CYP2E1, a metabolic enzyme of CCl4, was also not significantly affected by rotenone. In conclusion, rotenone protected the liver from CCl4-induced damage possibly by inhibiting the mitochondrial oxidative stress and inflammation.