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Abstract
Yeast Saccharomyces cerevisiae grown on glucose undergoes programmed cell death (PCD) induced by acetic acid (AA-PCD), but evades PCD when grown in raffinose. This is due to concomitant relief of carbon catabolite repression (CCR) and activation of mitochondrial retrograde signaling, a mitochondria-to-nucleus communication pathway causing up-regulation of various nuclear target genes, such as CIT2, encoding peroxisomal citrate synthase, dependent on the positive regulator RTG2 in response to mitochondrial dysfunction. CCR down-regulates genes mainly involved in mitochondrial respiratory metabolism. In this work, we investigated the relationships between the RTG and CCR pathways in the modulation of AA-PCD sensitivity under glucose repression or de-repression conditions. Yeast single and double mutants lacking RTG2 and/or certain factors regulating carbon source utilization, including MIG1, HXK2, ADR1, CAT8, and HAP4, have been analyzed for their survival and CIT2 expression after acetic acid treatment. ADR1 and CAT8 were identified as positive regulators of RTG-dependent gene transcription. ADR1 and CAT8 interact with RTG2 and with each other in inducing cell resistance to AA-PCD in raffinose and controlling the nature of cell death. In the absence of ADR1 and CAT8, AA-PCD evasion is acquired through activation of an alternative factor/pathway repressed by RTG2, suggesting that RTG2 may play a function in promoting necrotic cell death in repressing conditions when RTG pathway is inactive. Moreover, our data show that simultaneous mitochondrial retrograde pathway activation and SNF1-dependent relief of CCR have a key role in central carbon metabolism reprogramming which modulates the yeast acetic acid-stress response.
Highlights
Glucose is by far the preferred carbon source of the budding yeast Saccharomyces cerevisiae, because glucose metabolic regulation dictates the organism's distinctive fermentative lifestyle—aerobic fermentation [1, 2]
Genetic inactivation of carbon catabolite repression (CCR) by MIG1 or HXK2 deletion does not affect sensitivity of yeast to acetic acid-induced programmed cell death (AA-programmed cell death (PCD)) Genes involved in CCR are of two types: genes such as HXK2 and MIG1, which are active in glucose-grown cells and repress certain transcription factors such as Hap4 and Cat8; genes required for de-repression, such as SNF1 and its downstream-activated transcription factors, Adr1 and Cat8, which are active in cells grown on alternative carbon sources, like raffinose (Fig. 1)
In order to investigate the relations between glucose repression and the determination of cell fate, we first analyzed the effect of MIG1 or HXK2 deletions on AA-PCD sensitivity under glucose repression conditions
Summary
Glucose is by far the preferred carbon source of the budding yeast Saccharomyces cerevisiae, because glucose metabolic regulation dictates the organism's distinctive fermentative lifestyle—aerobic fermentation (the Crabtree effect) [1, 2]. The phenomenon of glucose repression is a global regulatory mechanism causing inhibition of transcription of a large set of genes mainly involved in mitochondrial respiratory metabolism [3,4,5,6], which is known as the carbon catabolite repression (CCR) pathway. CCR is mediated, in part, by the crosstalk between two glucose signaling pathways: the RGT2/SNF3 axis responsible for glucose uptake [7,8,9]; and the SNF1/MIG1 axis that negatively regulates the genes involved in respiratory metabolism and the use of alternative sugars [3, 10, 11]. The RTG pathway has been implicated in the intracellular signaling network linking mitochondrial function and cellular metabolism to several physiological processes such as ageing [18], PCD [16], autophagy [19] and ceramide metabolism [20]
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