Attenuation of transcriptional and signaling responses limits viability of ρ(0)Saccharomyces cerevisiae during periods of glucose deprivation.
BACKGROUND
The 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.


METHODS
We 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 ρ(0) 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 ρ(0) cells.


RESULTS
The transcriptional response to glucose deprivation is dampened but not blocked in ρ(0) 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 ρ(0) cells. Regulation of the nutrient responsive kinases PKA and Snf1 remains normal in ρ(0) 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 ρ(0) cells during subsequent glucose deprivation.


CONCLUSIONS
A subset of nutrient responsive kinases is especially sensitive to ATP levels and their misregulation may underlie regulatory defects presented by ρ(0) 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.
['Friis|R Magnus N|RMN|', 'Schultz|Michael C|MC|']
D002455:Cell Division D004272:DNA, Mitochondrial D015966:Gene Expression Regulation, Fungal D005947:Glucose D000071679:Glycogen Synthase Kinase 3 beta D047908:Intracellular Signaling Peptides and Proteins D011494:Protein Kinases D017346:Protein Serine-Threonine Kinases D012441:Saccharomyces cerevisiae D029701:Saccharomyces cerevisiae Proteins D015398:Signal Transduction D015533:Transcriptional Activation
Transcription Signaling Viability Glucose Mitochondria Yeast.