Mitochondrial DNA Abundance is Maintained by APE1 in Liver of Mice Treated with AOM

Abstract

Background The liver is the body's largest internal organ which performs many metabolic processes, including detoxification of several classes of carcinogens. Because of the numerous critical functions performed by the liver, degenerative liver diseases such as hepatitis, cirrhosis, and liver cancer are especially life-threatening. Previous research indicates, that in liver cancer, mitochondrial function is altered. Base Excision Repair (BER) is the primary mechanism for the repair of alkylation and oxidative DNA damage in mitochondria. Our research is focusing on the study of the protein apurinic/apyrimidinic endonuclease 1 (APE 1). The alkylating agent azoxymethane (AOM) is a carcinogen widely used for the induction of colorectal cancer in rodents. AOM is bioactivated in the liver, thus this organ could represent a primary target of AOM action and a model for liver carcinogenesis. Objective To assess the effect of AOM in mtDNA abundance in liver tissue from mice deficient in the main abasic site endonuclease APE1. Hypothesis Mitochondrial DNA (mtDNA) abundance will be altered in liver tissue after AOM treatment. Methods Two strains of mice were analyzed, a Wild Type (WT) strain and another carrying a null mutation of one allele of the DNA repair gene APE1 (Apex1+/-). Animals were exposed to 4 doses of AOM (10mg/kg body weight once a week for 4 weeks) and liver tissue was harvested 6 months after the first AOM treatment. MtDNA abundance was analyzed by real-time PCR. Results We observed a 30% decreased in mtDNA abundance in liver tissue from Apex1+/- mice chronically treated with AOM when compared to its control, while in WT animals mtDNA abundance was unchanged. Conclusion Our results indicate that chronic AOM treatment in DNA repair deficient mice results in decreased mtDNA abundance in liver tissue. Further research will focus on the consequences of loss of mtDNA abundance in mitochondrial function.