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.
Highlights
Reduction of calorie intake, known as calorie restriction (CR), is the only physiological intervention that universally extends lifespan
Protein Kinase A (PKA) activation is necessary for the transcriptional reprogramming occurring upon glucose addition to cells growing on poor carbon sources (Zaman, Lippman, Schneper, Slonim, & Broach, 2009)
In addition to pH control of PKA, PKA was found to regulate both plasma membrane and vacuolar H+‐pumps, Pma1 and V‐ATPase (Bond & Forgac, 2008; Souza, Trópia, & Brandão, 2001), which suggests a role of PKA in pHc control. We address this question and show that pHc is controlled by PKA in a glucose concentration‐ dependent manner and that these changes in pHc are an important determinant of calorie restriction control of Chronological lifespan (CLS)
Summary
Known as calorie restriction (CR), is the only physiological intervention that universally extends lifespan. Glucose addition to de‐repressed cultures induces a transient cAMP increase by the activation of adenylate cyclase (Cyr1) via two branches of the pathway: Ras and the G protein‐coupled receptor system Of these two branches, only Ras signalling is essential for PKA activation and growth (Conrad et al, 2014). Glucose addition to starved cells itself causes a transient cytosolic acidification, in a timescale similar to the cAMP peak (Tarsio, Zheng, Smardon, Martínez‐ Muñoz, & Kane, 2011) Whether it is the glucose‐dependent transient acidification that triggers cAMP induction upon glucose re‐ addition remains unclear; the two have been suggested to be independent, kinetic analyses reveal that the pHc decrease precedes the cAMP response (Thevelein et al, 1987).
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