科研之友
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摘要
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 rho(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 rho(0) cells. Results: The transcriptional response to glucose deprivation is dampened but not blocked in rho(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 rho(0) cells. Regulation of the nutrient responsive kinases PKA and Snf1 remains normal in rho(0) cells. The phosphorylation defect results from ATP depletion and loss of the activity of kinases including GSK3 beta, Rim15, and Yak1. Interventions which rescue phosphoregulation of transcription factors bolster maintenance of viability in rho(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 rho(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.
- 出版日期2016-11
