Crosstalk between RTG and TOR pathways mediates adaptation to amino acid starvation during fermentative growth in Saccharomyces cerevisiae

Abstract In the presence of glucose, Saccharomyces cerevisiae prefers glycolysis followed by fermentation to generate ATP. One adaptation to this fermentative lifestyle is the retrograde pathway (RTG), which induces the transcription of genes, including several Krebs cycle genes, to increase pools of alpha-ketoglutarate. We previously found that both petite and RTG mutants are highly sensitive to canavanine, a toxic analog of arginine, indicating that residual respiration and the RTG pathway are required to maintain arginine levels in the cell. Yet, from an amino acid biosynthesis standpoint, it is unclear how the RTG pathway balances between respiration and fermentation. Here, we show that use of a non-fermentable carbon source restored RTG mutants’ ability to grow without arginine or lysine and improved their growth on canavanine and thialysine. Relief of glucose repression via deletion of MIG1 improved RTG mutant growth on agar under arginine or lysine limitation but was not sufficient to restore growth on a toxic analog. rtg2Δ exhibited more canavanine sensitivity than other RTG mutants, was not rescued by mig1Δ, and was only partially rescued by mks1Δ, suggesting that Rtg2 may have an additional function required for canavanine tolerance. Target of rapamycin (TOR) signaling as a pro-growth factor suppresses the RTG pathway, but it is unknown if both pathways complement each other. We found that TOR signaling contributes to canavanine tolerance in an RTG-independent manner. The broad implications of our results are found in the importance of fermentative lifestyle under amino acid starvation as part of industrial and malignant ecosystems.