title: Caloric Restriction Extends Yeast Chronological Life Span by Optimizing the Snf1 (AMPK) Signaling Pathway.
abstract: AMP-activated protein kinase (AMPK) and the homologous yeast SNF1 complex are key regulators of energy metabolism that counteract nutrient deficiency and ATP depletion by phosphorylating multiple enzymes and transcription factors that maintain energetic homeostasis. AMPK/SNF1 also promotes longevity in several model organisms, including yeast. Here we investigate the role of yeast SNF1 in mediating the extension of chronological life span (CLS) by caloric restriction (CR). We find that SNF1 activity is required throughout the transition of log phase to stationary phase (diauxic shift) for effective CLS extension. CR expands the period of maximal SNF1 activation beyond the diauxic shift, as indicated by Sak1-dependent T210 phosphorylation of the Snf1 catalytic α-subunit. A concomitant increase in ADP is consistent with SNF1 activation by ADPin vivoDownstream of SNF1, the Cat8 and Adr1 transcription factors are required for full CR-induced CLS extension, implicating an alternative carbon source utilization for acetyl coenzyme A (acetyl-CoA) production and gluconeogenesis. Indeed, CR increased acetyl-CoA levels during the diauxic shift, along with expression of both acetyl-CoA synthetase genesACS1andACS2We conclude that CR maximizes Snf1 activity throughout and beyond the diauxic shift, thus optimizing the coordination of nucleocytosolic acetyl-CoA production with massive reorganization of the transcriptome and respiratory metabolism.
authors.affiliation: Department of Biochemistry and Molecular Genetics, University of Virginia School of Medicine, Charlottesville, Virginia, USA.
authors.forename: Margaret B
authors.initials: MB
authors.lastname: Wierman
authors.affiliation: Department of Biochemistry and Molecular Genetics, University of Virginia School of Medicine, Charlottesville, Virginia, USA.
authors.forename: Nazif
authors.initials: N
authors.lastname: Maqani
authors.affiliation: Department of Biochemistry and Molecular Genetics, University of Virginia School of Medicine, Charlottesville, Virginia, USA.
authors.forename: Erika
authors.initials: E
authors.lastname: Strickler
authors.affiliation: Department of Biochemistry and Molecular Genetics, University of Virginia School of Medicine, Charlottesville, Virginia, USA.|Department of Laboratory Medicine, Jilin Medical University, Jilin, China.
authors.forename: Mingguang
authors.initials: M
authors.lastname: Li
authors.affiliation: Department of Biochemistry and Molecular Genetics, University of Virginia School of Medicine, Charlottesville, Virginia, USA jss5y@virginia.edu.
authors.forename: Jeffrey S
authors.initials: JS
authors.lastname: Smith
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000378:metabolism*; D000105:Acetyl Coenzyme A / Q000235:genetics / Q000378:metabolism*; D004734:Energy Metabolism; D008018:Life Cycle Stages; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D012441:Saccharomyces cerevisiae / Q000502:physiology*; D029701:Saccharomyces cerevisiae Proteins / Q000378:metabolism*; D015398:Signal Transduction
chemical_list: D029701:Saccharomyces cerevisiae Proteins; D000105:Acetyl Coenzyme A; C071570:SNF1-related protein kinases; D017346:Protein Serine-Threonine Kinases; D055372:AMP-Activated Protein Kinases
keywords: ADP; AMPK; Snf1; acetyl-CoA; aging; caloric restriction; diauxic shift; yeast