The High-Osmolarity Glycerol (HOG) and Mitochondrial Retrograde (RTG) signaling interplay in yeast adaptive stress response

Different stressful conditions threatening cell homeostasis trigger molecular responses that can result either in cell adaptation to the newly-formed conditions and survival, or can cause cell death. The adaptive capacity of a cell is the result of the integration of multiple signals in response to different environmental cues with a major role played by mitochondria. Defects in cell components and pathways involved in stress response can lead to cancer and other diseases. Since yeast can undergo programmed cell death (PCD) which shares similar features with mammalian apoptosis, it is a valuable model organism to investigate cell stress response. Our research hasbeen focused on the role of mitochondria in the integration of environmental cues to activate certain signaling pathways regulating cell fate. We have used an experimental system in which PCD is induced by acetic acid(AA-PCD) in yeast cells grown in glucose. AA-PCD occurs through a mitochondrial pathway involving oxygen species accumulation, cytochrome c release, mitochondrial dysfunction and culminating in DNA fragmentation and a complete loss of cell viability. We have found that, differently from glucose-grown cells,raffinose-grown cells were mostly resistant to AA-PCD due to the activation of mitochondrial retrograde (RTG)response, as revealed by the up-regulation of the RTG-pathway target gene CIT2, encoding for peroxisomal isoform of citrate synthase, favored by the lack of glucose repression. In another experimental setup we inducedan adaptive response which protected yeast from AA-PCD through cell pre-conditioning in culture medium set at pH 3.0 with HCl prior to AA treatment. Inactivation of either RTG or High-Osmolarity Glycerol (HOG) pathwayby RTG2 or HOG1 gene deletion, respectively, restored AA-PCD. RTG2- and HOG1-target gene expression was analyzed both in non-adapted and adapted cells during AA-treatment to elucidate how the two stress response pathways interplay in acid stress adaptation. Overall our results show that extracellular environment can profoundly affect the initiation of adaptive stress response and consequently the sensitivity to AA-PCD. This work has been funded by grants from project FIRB-MERIT BNE08HWLZ, the Italian Ministry ofEconomy and Finance to the CNR for the Project “FaReBio di Qualità” and project BioNet –PTP - PO Regione Puglia FESR 2000-2006.