Abstract 3373: Contribution of microRNA-122 to the homeostasis of liver energy metabolism

Abstract

Abstract MicroRNA-122 (miR-122) is a liver specific miRNA known to regulate lipid metabolism and to prevent liver tumorigenesis. Recent data suggest that miR-122 regulates the metabolism of mitochondria but its mechanistic role is unclear. We investigated how energy metabolism is regulated by miR-122 using the Mir122a-/- mouse model. We identified a distinctive expression profile of mitochondrially localized genes between WT and Mir122a-/- mice by both microarray and proteomics. KEGG and IPA database analysis further showed decreased mitochondrial respiration activity and Acetyl-CoA synthesis. Besides, the expression of genes involved in antioxidant mechanism is increased. The primary hepatocytes were used to study the energy metabolism. The physiological activities measured by XF-24 extracellular flux analyzer revealed a higher mitochondrial respiration activity (OCR) accompanied with a proton leak in the mitochondrial inner membrane of the Mir122a-/- hepatocytes. In addition, a higher glycolytic activity (ECAR) was detected in Mir122a-/- hepatocytes. Poor ATP production was detected from Mir122a-/- mitochondria. Several lines of evidence demonstrated that Mir122a-/- hepatocytes have low mitochondria membrane potential: excess cytosolic reactive oxygen species, less mitochondrial superoxide anion and lower staining with Rhodamine 123 and Mitotracker red. We further treated cells with mitochondrial inhibitors and found an excellent antioxidant capacity and ATP homeostasis in Mir122a-/- primary hepatocytes. Interestingly, we detected lower protein expression of pyruvate dehydrogenase complex subunit E1, which may partly contribute to the defective mitochondrial activity. The liver homeostasis of Mir122a-/- mice, however, is stabilized by a vigorous antioxidant activity and higher glycolysis capacity. As a result, the livers of young Mir122a-/- mice appear to have switched to aerobic glycolysis (Warburg effect), which is the hallmark of cancer cells. Therefore, correction of mitochondrial dysfunction is likely to become one of new therapeutic means for hepatocellular carcinoma (HCC). Citation Format: Ann-Ping Tsou, Shuo-Ting Wang, Tse-Wen Tao. Contribution of microRNA-122 to the homeostasis of liver energy metabolism. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 3373. doi:10.1158/1538-7445.AM2014-3373