Mitochondria-targeted antioxidant, mito-TEMPO mitigates initiation phase of N-Nitrosodiethylamine-induced hepatocarcinogenesis

Abstract

Targeting mitochondrial oxidative stress during initial stages of hepatocarcinogenesis can be an effective and promising strategy to prevent hepatocellular carcinoma (HCC). In the present study, mitochondria targeted antioxidant, mito-TEMPO was administered to male BALB/c mice at a dosage 0.1 mg/kg b.w. (intraperitoneal) twice a week, followed by single N-Nitrosodiethylamine (NDEA) intraperitoneal injection (10 mg/kg b.w.). After 24 h of NDEA administration, animals were sacrificed, blood and liver tissue were collected. Liver injury markers, histoarchitecture, antioxidant defence status, mitochondrial reactive oxygen species (ROS), lipid peroxidation (LPO), mitochondrial dysfunction analysis, and mitochondrial membrane potential were investigated. Mito-TEMPO pre-treatment protected animals from the damaging effects of NDEA as observed by normalization of liver injury markers. NDEA metabolism resulted in a significantly increased intracellular and mitochondrial ROS generation with concomitant increase in LPO formation. The activity of mitochondrial complex I, complex II, malate dehydrogenase were significantly reduced and mitochondrial membrane potential was increased. Mito-TEMPO effectively scavenged NDEA-induced ROS generation and reduced LPO formation. A significant improvement was also observed in the activity of mitochondrial complex I, complex II, malate dehydrogenase and normalisation of mitochondrial membrane potential. Results suggested that mito-TEMPO had significant impact on the initiation phase of hepatocarcinogensis which could be one of the reason for its reported chemopreventive effect.

Keywords: Mito-TEMPO; Mitochondria; N-Nitrosodiethylamine (NDEA); Oxidative stress.