Caloric restriction controls stationary phase survival through Protein Kinase A (PKA) and cytosolic pH

Abstract

Calorie restriction is the only physiological intervention that extends lifespan throughout all kingdoms of life. In the budding yeast Saccharomyces cerevisiae, cytosolic pH (pHc) controls growth and responds to nutrient availability, decreasing upon glucose depletion. We investigated the interactions between glucose availability, pHc and the central nutrient signalling cAMP‐Protein Kinase A (PKA) pathway. Glucose abundance during the growth phase enhanced acidification upon glucose depletion, via modulation of PKA activity. This actively controlled reduction in starvation pHc correlated with reduced stationary phase survival. Whereas changes in PKA activity affected both acidification and survival, targeted manipulation of starvation pHc showed that cytosolic acidification was downstream of PKA and the causal agent of the reduced chronological lifespan. Thus, caloric restriction controls stationary phase survival through PKA and cytosolic pH.

Physiological responses of Saccharomyces cerevisiae to industrially relevant conditions: Slow growth, low pH, and high CO2 levels

“…In particular, high CO 2 levels appeared to dampen the transcriptional response to low pH. Low pH stress triggers transcriptional regulation of genes under control of the cell wall integrity (CWI), high‐osmolarity glycerol (HOG) and calcineurin signaling pathways (de Lucena et al, ) and cytosolic pH acts as a sensor for PKA‐signaling (Dolz‐Edo, Guikema‐van der Deen, Brul, & Smits, ; Orij et al, ). Additionally, sensing of CO 2 is relayed through sphingolipid‐mediated sensing, via the kinases Pkh1 and Pkh2, to the central nutrient sensor Sch9 (Pohlers et al, ).…”

“…Second, at high extracellular CO 2 conditions bicarbonate accumulates intracellularly, improves buffering of the cytosol, and attenuates the cytosolic pH (Buck & Levin, ; Eigenstetter & Takors, ). Both the cytosolic pH and bicarbonate are direct signals for PKA signaling (Buck & Levin, ; Dolz‐Edo et al, ; Thomas, ). Phosphoproteomic analysis of the proteins in the CWI, HOG, and PKA signaling pathways could prove an efficient strategy to elucidate the observed interplay of high CO 2 and low pH signaling (Mascaraque et al, ), which could be supported by analysis of the in vivo cytosolic pH at high CO 2 and low pH conditions by the pH‐dependent GFP‐derivative pHluorin (Orij et al, ).…”

“…Both the cytosolic pH and bicarbonate are direct signals for PKA signaling (Buck & Levin, 2011;Dolz-Edo et al, 2019;Thomas, 1976). Phosphoproteomic analysis of the proteins in the CWI, HOG, and PKA signaling pathways could prove an efficient strategy to elucidate the observed interplay of high CO 2 and low pH signaling (Mascaraque et al, 2013), which could be supported by analysis of the in vivo cytosolic pH at high CO 2 and low pH conditions by the pH-dependent GFP-derivative pHluorin .…”

Aberrant Intracellular pH Regulation Limiting Glyceraldehyde-3-Phosphate Dehydrogenase Activity in the Glucose-Sensitive Yeast tps1 Δ Mutant

“…The catalytic site of GAPDH is known to be very sensitive to oxidation, causing glycolytic flux to be rerouted to the pentose phosphate pathway for increased production of NADPH to combat ROS toxicity ( 31 , 32 ). Interestingly, several conditions that are associated with increased ROS production, such as carbon starvation and the stationary phase ( 55 ), are associated with lowered cytosolic pH ( 53 , 56 ).…”

Ebselen as a highly active inhibitor of PLProCoV2

“…Another recently published work proposed via virtual screening ebselen as a possible inhibitor of M pro from SARS-CoV-2 [21]. Several lines of evidence demonstrated the biological effects of ebselen is mainly due to its antioxidant properties and capability of forming selenenyl-sulfide bonds with the cysteine residues in proteins [16,[22][23][24][25].…”