title: Inorganic pyrophosphatase defects lead to cell cycle arrest and autophagic cell death through NAD+ depletion in fermenting yeast.
abstract: Inorganic pyrophosphatases are required for anabolism to take place in all living organisms. Defects in genes encoding these hydrolytic enzymes are considered inviable, although their exact nature has not been studied at the cellular and molecular physiology levels. Using a conditional mutant in IPP1, the Saccharomyces cerevisiae gene encoding the cytosolic soluble pyrophosphatase, we show that respiring cells arrest in S phase upon Ipp1p deficiency, but they remain viable and resume growth if accumulated pyrophosphate is removed. However, fermenting cells arrest in G1/G0 phase and suffer massive vacuolization and eventual cell death by autophagy. Impaired NAD(+) metabolism is a major determinant of cell death in this scenario because demise can be avoided under conditions favoring accumulation of the oxidized pyridine coenzyme. These results posit that the mechanisms related to excess pyrophosphate toxicity in eukaryotes are dependent on the energy metabolism of the cell.
authors.affiliation: Instituto de Bioquímica Vegetal y Fotosíntesis, Universidad de Sevilla-Consejo Superior de Investigaciones Científicas (CSIC), Avda. Américo Vespucio 49, 41092 Seville, Spain.
authors.forename: Gloria
authors.initials: G
authors.lastname: Serrano-Bueno
authors.forename: Agustín
authors.initials: A
authors.lastname: Hernández
authors.forename: Guillermo
authors.initials: G
authors.lastname: López-Lluch
authors.forename: José Román
authors.initials: JR
authors.lastname: Pérez-Castiñeira
authors.forename: Plácido
authors.initials: P
authors.lastname: Navas
authors.forename: Aurelio
authors.initials: A
authors.lastname: Serrano
mesh_terms: D001343:Autophagy / Q000502:physiology*; D011756:Diphosphates / Q000378:metabolism; D004734:Energy Metabolism / Q000502:physiology*; D043564:Inorganic Pyrophosphatase / Q000235:genetics / Q000378:metabolism*; D009243:NAD / Q000235:genetics / Q000378:metabolism*; D059807:S Phase Cell Cycle Checkpoints / Q000502:physiology*; D012441:Saccharomyces cerevisiae / Q000201:enzymology* / Q000235:genetics; D029701:Saccharomyces cerevisiae Proteins / Q000235:genetics / Q000378:metabolism*
chemical_list: D011756:Diphosphates; D029701:Saccharomyces cerevisiae Proteins; D009243:NAD; C107241:diphosphoric acid; C470575:IPP1 protein, S cerevisiae; D043564:Inorganic Pyrophosphatase
keywords: Autophagy; Cell Death; Energy Metabolism; NAD; Yeast Metabolism