| Summary: | 碩士 === 國立陽明大學 === 醫學生物技術暨檢驗學系 === 102 === MicroRNA-122 (miR-122) is a liver specific miRNA known to participate in lipid metabolism and tumorigenesis. Previously, it was reported that that miR-122 can regulate the mitochondrial activity. The mechanism by which miR-122 modulates mitochondrial function is not well understood. This study was designed to investigate how energy metabolism is regulated by miR-122 using the Mir122a–/– mouse model.
We identified a distinctive expression profile of mitochondrially-localized genes in Mir122a–/– mice by both microarray and proteomics. KEGG and IPA analyses showed decreased mitochondrial function and acetyl-CoA synthesis, while the expression of genes involved in antioxidant mechanism is increased.
The primary hepatocytes were used to study the energy metabolism. The physiological activities measured with XF-24 extracellular flux analyzer revealed higher mitochondrial oxygen consumption accompanied with a proton leak and a higher glycolytic activity in the Mir122a–/– hepatocytes. Poor ATP production, however, was detected from Mir122a–/– mitochondria. Several lines of evidence demonstrated that Mir122a–/– hepatocytes have low mitochondrial membrane potential: less mitochondrial superoxide anion and lower staining with rhodamine 123 and mitotracker red.
To explore the mechanisms involved in the altered energy metabolism, we analyzed the expression of genes of glycolysis, the subunits of the pyruvate dehydrogenase complex (PDC) and of gluconeogenesis. Higher expression of glucose transporters may account for a potential higher glucose input for glycolysis. Notably, we detected lower gene expression of the PDC subunits but higher pyruvate dehydrogenase activity in the Mir122a–/– primary hepatocytes. The PDC controls the conversion of pyruvate to acetyl-CoA which is a key step to aerobic respiration. These results suggest that loss of miR-122a may have elicited a higher PDC activity to compensate the mitochondrial defect observed in Mir122a-/- hepatocytes. The detailed mechanisms, however, remain to be determined.
In summary, an altered PDC activity and the higher respiration rate are unique features of the Mir122a–/– liver mitochondria. The liver homeostasis of Mir122a–/– mice, nonetheless, is stabilized by higher glycolysis capacity and vigorous antioxidant activity. As a result, the livers of young Mir122a–/– mice appear to have conformed to the anaerobic glycolysis, the so-called 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).
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