pH homeostasis links the nutrient sensing PKA/TORC1/Sch9 ménage-à-trois to stress tolerance and longevity

Abstract

The plasma membrane H+-ATPase Pma1 and the vacuolar V-ATPase act in close harmony to tightly control pH homeostasis, which is essential for a vast number of physiological processes. As these main two regulators of pH are responsive to the nutritional status of the cell, it seems evident that pH homeostasis acts in conjunction with nutrient-induced signalling pathways. Indeed, both PKA and the TORC1-Sch9 axis influence the proton pumping activity of the V-ATPase and possibly also of Pma1. In addition, it recently became clear that the proton acts as a second messenger to signal glucose availability via the V-ATPase to PKA and TORC1-Sch9. Given the prominent role of nutrient signalling in longevity, it is not surprising that pH homeostasis has been linked to ageing and longevity as well. A first indication is provided by acetic acid, whose uptake by the cell induces toxicity and affects longevity. Secondly, vacuolar acidity has been linked to autophagic processes, including mitophagy. In agreement with this, a decline in vacuolar acidity was shown to induce mitochondrial dysfunction and shorten lifespan. In addition, the asymmetric inheritance of Pma1 has been associated with replicative ageing and this again links to repercussions on vacuolar pH. Taken together, accumulating evidence indicates that pH homeostasis plays a prominent role in the determination of ageing and longevity, thereby providing new perspectives and avenues to explore the underlying molecular mechanisms.

Fungal plasma membrane domains

“…As mentioned before, the main roles of Pma1 is to energize the PM and control the intracellular pH (Kane 2016). The latter function is also influenced by the Vacuolar-type H + -ATPase (V-ATPase), a multi-subunit enzyme pumping protons from the cytosol into the lumen of acidic organelles such as vacuoles/lysosomes, endosomes and Golgi compartments in all eukaryotic cells [Reviewed in (Deprez et al 2018)]. It is therefore not surprising that the V-ATPase and Pma1 are highly interdependent pumps that act in close harmony.…”

Conventional and emerging roles of the energy sensor Snf1/AMPK in Saccharomyces cerevisiae

“…In yeast, the main pathway activated by glucose is the PKA pathway, involved in metabolism, growth and proliferation 71 72 73 . Targets of PKA include glycolytic and gluconeogenetic enzymes, proteins involved in the metabolism of storage carbohydrates, transcription factors regulating stress response, ribosomal biogenesis, and carbohydrate metabolism.…”

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

“…Additionally, sensing of CO 2 is relayed through sphingolipidmediated sensing, via the kinases Pkh1 and Pkh2, to the central nutrient sensor Sch9 (Pohlers et al, 2017). Extensive crosstalk between these signaling pathways enables cellular homeostasis (Chen & Thorner, 2007;Deprez, Eskes, Wilms, Ludovico, & Winderickx, 2018;Flamigni & Dolci, 2010;Fuchs & Mylonakis, 2009;Rodriguez-Pena, Garcia, Nombela, & Arroyo, 2010). Accordingly, genes under control of the transcription factors regulated by these signaling pathways (Skn7p, Rlm1p, Sko1p, Figures 6e, 6h, 6i, and 6j) were upregulated at pH 3, as were gene sets involved in cell wall synthesis (Lesage & Bussey, 2006) and cell wall stress (Boorsma et al, 2004).…”