DOI: 10.23902/trkjnat.2045953 ISSN: 2147-0294

Role of yeast MIG1 gene in glycolysis, mitochondrial bioenergetics, and glycogen and trehalose biosynthesis in response to DNA damage

Van Ngoc Bui, Duc Duy Nguyen, Hong Phuc Cao, Trung Hieu Bui, Hoang Ha Chu, Thi Thu Huyen Nguyen
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Background: In eukaryotic cells, under certain stress conditions, the diversion of carbohydrate flux, either downstream toward tricarboxylic acid (TCA) cycle or upstream toward the hexosamine biosynthesis and pentose phosphate pathways, is governed by the activation of key regulatory genes and glycolytic enzymes. In Saccharomyces cerevisiae, the transcription factor Mig1 (encoded by the MIG1 gene) regulates respiration, glucose repression, and gluconeogenesis. In addition, Mig1 pathway represses Hap2p/3p/4p/5p complex, thereby modulating genes involved in the TCA cycle and mitochondrial electron transport chain. Aims: This study aimed to investigate the role of the MIG1 gene in regulating glycolysis, mitochondrial bioenergetics/respiration, and reserve carbohydrate biosynthesis in response to DNA damage. Methods: The wild type (BY4742) and specific knock-out (∆mig1) Saccharomyces cerevisiae strains were treated with methyl methanesulfonate (MMS) to induce DNA damage. Cellular responses were analyzed by using flow cytometry, chromatography, OxoPlate®, gloxo, and enzymatic assays. Results: The deletion of MIG1 fundamentally impaired the mitochondrial electron transport chain and reduced oxygen consumption, which rendered the Δmig1 mutant highly susceptible to MMS-induced genotoxic stress. This deficiency triggered an elevated accumulation of reactive oxygen species (ROS), which associated with inhibition of glyceraldehyde-3-phosphate dehydrogenase (GAPDH) and pyruvate kinase (PYK) activities, thereby decreasing downstream ATP production. To counteract this energy crisis and support cellular signaling during the DNA damage response, carbohydrate flux bypassed standard glycolysis and the TCA cycle. Instead, glucose was redirected upstream toward the pentose phosphate pathway via enhanced glucose-6-phosphate dehydrogenase (G6PDH) activity, shunted into the hexosamine biosynthesis pathway to yield elevated uridine diphosphate N-acetylglucosamine (UDP-NacGlu) levels, and ultimately diverted into gluconeogenesis or storage as glycogen and trehalose reserves. Conclusion: MMS-treated ∆mig1 cells promoted glycogen and trehalose synthesis more intensively than the MMS-treated wild type. These reserve carbohydrates act as readily mobilized storage form of glucose for cell survival of the ∆mig1 mutant cells.

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