Attenuation of transcriptional and signaling responses limits viability of ρ0Saccharomyces cerevisiae during periods of glucose deprivation

Abstract

BackgroundThe maintenance of viability during periods when a glycolytic carbon source is limited (or absent) is a major obstacle for cells whose mitochondrial DNA (mtDNA) has been damaged or lost. MethodsWe utilized genome wide transcriptional profiling and in gel mobility analyses to examine the transcriptional response and characterize defects in the phosphorylation dependent signaling events that occur during acute glucose starvation in ρ0 cells that lack mtDNA. Genetic and pharmacological interventions were employed to clarify the contribution of nutrient responsive kinases to regulation of the transcription factors that displayed abnormal phosphoregulation in ρ0 cells. ResultsThe transcriptional response to glucose deprivation is dampened but not blocked in ρ0 cells. Genes regulated by the transcription factors Mig1, Msn2, Gat1, and Ume6 were noticeably affected and phosphorylation of these factors in response to nutrient depletion is abnormal in ρ0 cells. Regulation of the nutrient responsive kinases PKA and Snf1 remains normal in ρ0 cells. The phosphorylation defect results from ATP depletion and loss of the activity of kinases including GSK3β, Rim15, and Yak1. Interventions which rescue phosphoregulation of transcription factors bolster maintenance of viability in ρ0 cells during subsequent glucose deprivation. ConclusionsA subset of nutrient responsive kinases is especially sensitive to ATP levels and their misregulation may underlie regulatory defects presented by ρ0 cells.General significance: Abnormal regulation of mitochondrial function is implicated in numerous human disorders. This work illustrates that some signaling pathways are more sensitive than others to metabolic defects caused by mitochondrial dysfunction.