Mitoquinol mesylate alleviates oxidative damage in cirrhotic and advanced hepatocellular carcinogenic rats through mitochondrial protection and antioxidative effects

Abstract

Mitochondrial dysfunction due to oxidative stress is usually implicated in pathological conditions such as cirrhosis and hepatocellular carcinoma (HCC). This study investigated the chemopreventive and therapeutic effects of mitochondrial targeted antioxidant, Mitoquinol Mesylate (MitoQ) in a model of diethylnitrosamine (DEN)-induced cirrhosis and advanced HCC. Liver cirrhosis and advanced HCC were induced in Wistar rats by diethylnitrosamine administration (10 mg/Kg/day, oral gavage) for 12 and 20 weeks, respectively. The cirrhotic and advanced HCC rats were treated with mitoQ (10 mg/Kg/day, oral gavage) as intervention therapy for 12-20 weeks (pre-treatment) and 4-12 weeks (post-treatment), respectively. Both MitoQ interventions improved body weight, survival index and hepatic function while reducing hepatosomatic index and nodular incidence in cirrhotic and advanced HCC rats. Pre-treatment with mitoQ suppressed the transformation of cirrhotic cells to malignancy and decreased the level of cirrhosis and HCC biomarkers. Also, pre-treatment restored the perturbations in lipid profile, mitochondrial dysfunction and oxidative stress induced by DEN-administration. MitoQ achieved these by modulating the activities of cytosolic and mitochondrial antioxidant enzymes as well as the expression of mitochondrial SOD2, GPX1 and CAT genes at both stages of cirrhosis and advanced HCC. Oral administration of MitoQ for 12 and 20 weeks further increased F₁F₀ATPase activity, suggesting mitochondrial respiratory chain uncoupling as one of its mechanisms of action. Therefore, MitoQ administration may represent a promising strategy for the prevention and treatment of liver cirrhosis and HCC by reducing hepatic oxidative stress and promoting removal of dysfunctional mitochondria.