Pma1, a P-type Proton ATPase, Is a Determinant of Chronological Life Span in Fission Yeast

Abstract

Chronological life span is defined by how long a cell can survive in a non-dividing state. In yeast, it is measured by viability after entry into stationary phase. To date, some factors affecting chronological life span have been identified; however, the molecular details of how these factors regulate chronological life span have not yet been elucidated clearly. Because life span is a complicated phenomenon and is supposedly regulated by many factors, it is necessary to identify new factors affecting chronological life span to understand life span regulation. To this end, we have screened for long-lived mutants and identified Pma1, an essential P-type proton ATPase, as one of the determinants of chronological life span. We show that partial loss of Pma1 activity not only by mutations but also by treatment with the Pma1 inhibitory chemical vanadate resulted in the longlived phenotype in Schizosaccharomyces pombe. These findings suggest a novel way to manipulate chronological life span by modulating Pma1 as a molecular target.In the natural environment, most microorganisms exhibit only brief periods of rapid growth. Nutrient starvation is the most common natural situation, so the ability to adapt to nutrient limitation is crucial for microorganisms. Cells respond to starvation by ceasing growth and entering stationary phase and differentiate in ways that allow them to maintain viability for extended periods in the absence of nutrients (1). In yeast, the period in which the cells keep their viability after entry into stationary phase is recognized as the chronological life span (2).In Saccharomyces cerevisiae, two of the major pathways that control chronological life span have been identified: the Ras-PKA-Msn2/4 pathway and the Sch9 pathway (3, 4). The downregulation of either pathway promotes life span extension. Importantly, similar pathways (insulin/insulin-like growth factor I-like) regulate longevity in higher eukaryotes, suggesting a common evolutionary origin for the life span regulatory mechanisms (5, 6).In Schizosaccharomyces pombe, Pka1 and Sck2 are regulators of chronological life span; each mutant shows a long-lived phenotype, and the pka1 sck2 double mutant displays an additive effect on chronological life span extension, suggesting that these two factors regulate related but independent pathways (7). We reported previously that a mutant of lcf1 ϩ , which encodes a long-chain fatty acyl-CoA synthetase, showed rapid loss of viability after entry into stationary phase and suggested that fatty acid utilization and/or metabolism is important to determine viability in stationary phase in fission yeast (8,9). Recently, we identified a novel gene, ecl1 ϩ , which extends the chronological life span of S. pombe when overexpressed (10). In addition, we also identified two paralogs and one ortholog of ecl1 ϩ in S. pombe and S. cerevisiae, respectively (11, 12). On the basis of these observations, we proposed that Ecl1 family proteins are novel regulators for chronological life span in yeast. Ecl1 family proteins ...

Chronological lifespan extension by Ecl1 family proteins depends on Prr1 response regulator in fission yeast

“…2005; Roux et al. 2006; Ito et al. 2010), and in accordance with this, ecl1 + ‐, ecl2 + ‐ and ecl3 + ‐over‐expressed cells also showed resistant phenotype to H 2 O 2 .…”

“…ecl1 + , ecl2 + and ecl3 + genes encode highly homologous small proteins, and they extend chronological lifespan of fission yeast when over-expressed, albeit their functions remain unclear. Interestingly, it is reported that many longlived mutants were more resistant to oxidative stress than wild type (Parkes et al 1998;Chen et al 2005;Schriner et al 2005;Roux et al 2006;Ito et al 2010), and in accordance with this, ecl1 + -, ecl2 + -and ecl3 + -over-expressed cells also showed resistant phenotype to H 2 O 2 . ecl1 + , ecl2 + and ecl3 + encode proteins with weak sequence homology to protein encoded by YGR146C in S. cerevisiae (Azuma et al 2009).…”

Aging and cell death in the other yeasts,Schizosaccharomyces pombeandCandida albicans

“…One possibility is that is that when vacuolar pH is high (old cells), proton‐facilitated amino acid (and other metabolites) transport into the vacuole is impaired leading to accumulation of intracellular amino acid (and other metabolites), which may depolarize mitochondrial membrane via an unknown mechanism (Hughes & Gottschling, ). Another study in S. pombe also supports the importance of intracellular pH maintenance in cellular life span (Ito et al ., ). Deleting a P‐type proton ATPase Pma1 decreases the export of H + and extends CLS.…”

“…Most of these longevity genes have homologs in S. cerevisiae , which contribute to the characterization of their roles in S. pombe CLS. These studies have associated CLS with nutrient signaling (Roux et al ., ; Ohtsuka et al ., ; Chen & Runge, ; Roux et al ., ; Ito et al ., ), mitochondrial activity/maintenance (Zuin et al ., ; Roux et al ., ,b; Azuma et al ., ; Ohtsuka et al ., ; Stephan et al ., ), ROS production/stress resistance (Mutoh & Kitajima, ; Zuin et al ., ,b; Ohtsuka et al ., , ), proteasome activity/redistribution, autophagy (Takeda & Yanagida, ; Takeda et al ., ), and vacuolar function (Stephan et al ., ). Many of these factors also play a role in low glucose CR‐induced CLS extension (Ohtsuka et al ., ; Chen & Runge, ; Roux et al ., ; Zuin et al ., ,b).…”

Construction of a photo-responsive chimeric histidine kinase in <i>Escherichia coli</i>

“…An antibody for ArcB was prepared by immunizing a rabbit with peptide RVRYDEGDMLHFEVEDSG, which corresponds to amino acids 422-439 of the ArcB protein and was purchased from Sigma ( Fig. 3A) (Ito et al, 2010). An antibody for KdpE was prepared by immunizing a rabbit with purified KdpE protein (Nakashima et al, 1992).…”