Beyond its classical biotechnological applications such as food and beverage production or as a cell factory, the yeast Saccharomyces cerevisiae is a valuable model organism to study fundamental mechanisms of cell response to stressful environmental changes. Acetic acid is a physiological product of yeast fermentation and it is a well-known food preservative due to its antimicrobial action. Acetic acid has recently been shown to cause yeast cell death and aging. Here we shall focus on the molecular mechanisms of S. cerevisiae stress adaptation and programmed cell death in response to acetic acid. We shall elaborate on the intracellular signaling pathways involved in the cross-talk of pro-survival and pro-death pathways underlying the importance of understanding fundamental aspects of yeast cell homeostasis to improve the performance of a given yeast strain in biotechnological applications.

Epithelial-to-mesenchymal transition (EMT) allows epithelial cancer cells to assume mesenchymal features, endowing them with enhanced motility and invasiveness, thus enabling cancer dissemination and metastatic spread. The induction of EMT is orchestrated by EMT-inducing transcription factors that switch on the expression of “mesenchymal” genes and switch off the expression of “epithelial” genes. Mitochondrial dysfunction is a hallmark of cancer and has been associated with progression to a metastatic and drug-resistant phenotype. The mechanistic link between metastasis and mitochondrial dysfunction is gradually emerging. The discovery that mitochondrial dysfunction owing to deregulated mitophagy, depletion of the mitochondrial genome (mitochondrial DNA) or mutations in Krebs’ cycle enzymes, such as succinate dehydrogenase, fumarate hydratase, and isocitrate dehydrogenase, activate the EMT gene signature has provided evidence that mitochondrial dysfunction and EMT are interconnected. In this review, we provide an overview of the current knowledge on the role of different types of mitochondrial dysfunction in inducing EMT in cancer cells. We place emphasis on recent advances in the identification of signaling components in the mito-nuclear communication network initiated by dysfunctional mitochondria that promote cellular remodeling and EMT activation in cancer cells.

Retrograde (RTG) signaling senses mitochondrial dysfunction and initiates readjustments of carbohydrate and nitrogen metabolism through nuclear accumulation of the heterodimeric transcription factors, Rtg1/3p. The RTG pathway is also linked to target of rapamycin (TOR) signaling, among whose activities is transcriptional control of nitrogen catabolite repression (NCR)-sensitive genes. To investigate the connections between these two signaling pathways, we have analyzed rapamycin sensitivity of the expression of the RTG target gene CIT2 and of two NCR-sensitive genes, GLN1 and DAL5, in respiratory-competent (ρ⁺) and -incompetent (ρ⁰) yeast cells. Here we have presented evidence that retrograde gene expression is separable from TOR regulation of RTG- and NCR-responsive genes. We showed that expression of these two classes of genes is differentially regulated by glutamate starvation whether in response to mitochondrial dysfunction or induced by rapamycin treatment, as well by glutamine or histidine starvation. We also showed that Lst8p, a component of the TOR1/2 complexes and a negative regulator of the RTG pathway, has multiple roles in the regulation of RTG- and NCR-sensitive genes. Lst8p negatively regulates CIT2 and GLN1 expression, whereas DAL5 expression is independent of Lst8p function. DAL5 expression depends on the GATA transcription factors Gln3p and Gat1p. Gat1p is translocated to the nucleus only upon TOR inhibition by rapamycin. Altogether, these data show that Rtg1/3p, Gln3p, and Gat1p can be differentially regulated through different nutrient-sensing pathways, such as TOR and retrograde signaling, and by multiple factors, such as Lst8p, which is suggested to have a role in connecting the RTG and TOR pathways.