Abstract 2911: APE1/Ref1, a mammalian DNA repair/redox factor, increases mitochondrial activity.

Abstract

Abstract The mammalian apurinic/apyrimidinic endonuclease 1 (APE1) is an essential DNA repair protein which also functions as a redox sensor (Ref1) to activate many transcription factors. A fraction of APE1/Ref1 protein is localized in the mitochondria for repairing oxidative DNA damage. However, its influence on mitochondrial activity has not been studied. We established genetically modified mouse embryonic fibroblast cells with extremely low APE1, at only 0.2% of the control MEFs. The APE1-knockdown (APE1kd) MEFs grew normally although they were highly sensitive to alkylating reagents. We analyzed the APE1kd MEFs to investigate the effect of APE1 on mitochondrial activity. Compared to the wild-type MEFs, the APE1kd MEFs exhibit a markedly decreased mitochondrial respiration activity and in turn showed glycolysis at a rate higher than the wild-type cells, which presumably compensated low ATP generation from mitochondria. A glycolysis inhibitor, 2-deoxy-D-glucose (2DG) affected ATP generation effectively, suggesting that the cells with low APE1 expression depended on glycolysis much more than the wild-type MEFs. The change in the mitochondrial activity appeared reversible. We propose that the presence of APE1 in the mitochondria/cytoplasm enhances mitochondrial respiration by a mechanism unrelated to its DNA repair activity. Citation Format: Suganya Rangaswamy, Chontida Yarana, Sumitra Miriyala, Tadahide Izumi. APE1/Ref1, a mammalian DNA repair/redox factor, increases mitochondrial activity. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 2911. doi:10.1158/1538-7445.AM2013-2911