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

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.Support via the research grants G.0694.13, G.0A63.15 and SBO-S006617N. We also thank KU Leuven for support by granting the C14/17/063 projectinfo:eu-repo/semantics/publishedVersio

The role of Sch9 and the V-ATPase in the adaptation response to acetic acid and the consequences for growth and chronological lifespan

Studies with Saccharomyces cerevisiae indicated that non-physiologically high levels of acetic acid promote cellular acidification, chronological aging, and programmed cell death. In the current study, we compared the cellular lipid composition, acetic acid uptake, intracellular pH, growth, and chronological lifespan of wild-type cells and mutants lacking the protein kinase Sch9 and/or a functional V-ATPase when grown in medium supplemented with different acetic acid concentrations. Our data show that strains lacking the V-ATPase are especially more susceptible to growth arrest in the presence of high acetic acid concentrations, which is due to a slower adaptation to the acid stress. These V-ATPase mutants also displayed changes in lipid homeostasis, including alterations in their membrane lipid composition that influences the acetic acid diffusion rate and changes in sphingolipid metabolism and the sphingolipid rheostat, which is known to regulate stress tolerance and longevity of yeast cells. However, we provide evidence that the supplementation of 20 mM acetic acid has a cytoprotective and presumable hormesis effect that extends the longevity of all strains tested, including the V-ATPase compromised mutants. We also demonstrate that the long-lived sch9∆ strain itself secretes significant amounts of acetic acid during stationary phase, which in addition to its enhanced accumulation of storage lipids may underlie its increased lifespan

Unconventional surface plasmon resonance signals reveal quantitative inhibition of transcriptional repressor EthR by synthetic ligands

International audienceEthR is a mycobacterial repressor that limits the bioactivation of ethionamide, a commonly used anti-tuberculosis second-line drug. Several efforts have been deployed to identify EthR inhibitors abolishing the DNA-binding activity of the repressor. This led to the demonstration that stimulating the bioactivation of ETH through EthR inhibition could be an alternative way to fight Mycobacterium tuberculosis. We propose a new SPR methodology to study the affinity between inhibitors and EthR. Interestingly, the binding between inhibitors and immobilized EthR produced a dose dependent negative SPR signal. We demonstrated that this signal reveals the affinity of the small molecules for the repressor. The affinity constants (KD) correlated with their capacity to inhibit the binding of EthR to DNA. We hypothesize that conformational changes of EthR during ligand interaction could be responsible for this SPR signal. Practically, this unconventional result open perspectives to the development of SPR assay that would at the same time tough on the structural changes of the target upon binding with an inhibitor and on the binding constant of this interaction

Light‐Induced Variations in AP‐1 Binding Activity and Composition in the Rat Suprachiasmatic Nucleus

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The TORC1-Sch9 pathway as a crucial mediator of chronological lifespan in the yeast Saccharomyces cerevisiae

The concept of ageing is one that has intrigued mankind since the beginning of time and is now more important than ever as the incidence of age-related disorders is increasing in our ageing population. Over the past decades, extensive research has been performed using various model organisms. As such, it has become apparent that many fundamental aspects of biological ageing are highly conserved across large evolutionary distances. In this review, we illustrate that the unicellular eukaryotic organism Saccharomyces cerevisiae has proven to be a valuable tool to gain fundamental insights into the molecular mechanisms of cellular ageing in multicellular eukaryotes. In addition, we outline the current knowledge on how downregulation of nutrient signaling through the target of rapamycin (TOR)-Sch9 pathway or reducing calorie intake attenuates many detrimental effects associated with ageing and leads to the extension of yeast chronological lifespan. Given that both TOR Complex 1 (TORC1) and Sch9 have mammalian orthologues that have been implicated in various age-related disorders, unraveling the connections of TORC1 and Sch9 with yeast ageing may provide additional clues on how their mammalian orthologues contribute to the mechanisms underpinning human ageing and health.status: publishe

Evidence for the presence of noradrenergic neurons and their inhibitory action on luteinizing hormone-releasing hormone release in cultured fetal rat hypothalamic cells

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Stimulatory Effects of 5HT1A Receptor Agonists on Luteinizing Hormone‐Releasing Hormone Release from Cultured Fetal Rat Hypothalamic Cells: Interactions with Progesterone

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Traitements des cancers superficiels de l'oesophage par voie endoscopique

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Serotonin directly stimulates luteinizing hormone‐releasing hormone release from GT1 cells via 5‐HT7 receptors

International audienceLuteinizing hormone‐releasing hormone (LHRH release, which serves as the primary drive to the hypothalamic‐pituitary gonadal axis, is controlled by many neuromediators. Serotonin has been implicated in this regulation. However, it is unclear whether the central effect of serotonin on LHRH secretion is exerted directly on LHRH neurosecretory neurons or indirectly via multisynaptic pathways. The present studies were undertaken in order to examine whether LHRH secretion from immortalized LHRH cell lines is directly regulated by serotonin and, if so, to identify the receptor subtype involved. 8‐hydroxy‐2‐(di‐n‐propylamino)tetralin (8‐OH‐DPAT), a 5‐HT1A/7 receptor agonist, stimulated LHRH release from GT1‐1 cells. This effect was blocked by ritanserin, a 5‐HT2/7 receptor antagonist, but not by SDZ‐216‐525, a 5‐HT1A antagonist. Basal LHRH release was not affected by the 5‐HT2 agonist DOI. Reverse transcription and polymerase chain reaction technique (RT‐PCR) was used in order to identify 5‐HT1A and 5‐HT7 receptor mRNA in immortalized LHRH cell lines. GT1‐1 cells express mRNA for the 5‐HT7, but not the 5‐HT1A receptor subtypes. These results demonstrate a direct stimulatory effect of serotonin on LHRH release via 5‐HT7 receptor