Multi-omics analyses of the transition to the Crabtree effect in S. cerevisiae reveals a key role for the citric acid shuttle

The Crabtree effect in the yeast, Saccharomyces cerevisiae, has been extensively studied, but only few studies have analyzed the dynamic conditions across the critical specific growth rate where the Crabtree effect sets in. Here, we carried out a multi-omics analysis of S. cerevisiae undergoing a specific growth rate transition from 0.2 h-1 to 0.35 h-1. The extracellular metabolome, the transcriptome and the proteome were analyzed in an 8-h transition period after the specific growth rate shifted from 0.2 h-1 to 0.35 h-1. The changing trends of both the transcriptome and proteome were analyzed using principal component analysis, which showed that the transcriptome clustered together after 60 min, while the proteome reached steady-state much later. Focusing on central carbon metabolism, we analyzed both the changes in the transcriptome and proteome, and observed an interesting changing pattern in the tricarboxylic acid (TCA) pathway, which indicates an important role for citric acid shuttling across the mitochondrial membrane for α-ketoglutarate accumulation during the transition from respiratory to respiro-fermentative metabolism. This was supported by a change in the oxaloacetate and malate shuttle. Together, our findings shed new light into the onset of the Crabtree effect in S. cerevisiae.