title: Rewiring AMPK and mitochondrial retrograde signaling for metabolic control of aging and histone acetylation in respiratory-defective cells.
abstract: Abnormal respiratory metabolism plays a role in numerous human disorders. We find that regulation of overall histone acetylation is perturbed in respiratory-incompetent (ρ(0)) yeast. Because histone acetylation is highly sensitive to acetyl-coenzyme A (acetyl-CoA) availability, we sought interventions that suppress this ρ(0) phenotype through reprogramming metabolism. Nutritional intervention studies led to the discovery that genetic coactivation of the mitochondrion-to-nucleus retrograde (RTG) response and the AMPK (Snf1) pathway prevents abnormal histone deacetylation in ρ(0) cells. Metabolic profiling of signaling mutants uncovered links between chromatin-dependent phenotypes of ρ(0) cells and metabolism of ATP, acetyl-CoA, glutathione, branched-chain amino acids, and the storage carbohydrate trehalose. Importantly, RTG/AMPK activation reprograms energy metabolism to increase the supply of acetyl-CoA to lysine acetyltransferases and extend the chronological lifespan of ρ(0) cells. Our results strengthen the framework for rational design of nutrient supplementation schemes and drug-discovery initiatives aimed at mimicking the therapeutic benefits of dietary interventions.
authors.affiliation: Department of Biochemistry, University of Alberta, Edmonton, AB T6G 2H7, Canada.
authors.forename: R Magnus N
authors.initials: RMN
authors.lastname: Friis
authors.affiliation: Department of Biochemistry, University of Alberta, Edmonton, AB T6G 2H7, Canada.
authors.forename: John Paul
authors.initials: JP
authors.lastname: Glaves
authors.affiliation: Department of Chemistry, University of Alberta, Edmonton, AB T6G 2H7, Canada.
authors.forename: Tao
authors.initials: T
authors.lastname: Huan
authors.affiliation: Department of Chemistry, University of Alberta, Edmonton, AB T6G 2H7, Canada.
authors.forename: Liang
authors.initials: L
authors.lastname: Li
authors.affiliation: Department of Biochemistry, University of Alberta, Edmonton, AB T6G 2H7, Canada.
authors.forename: Brian D
authors.initials: BD
authors.lastname: Sykes
authors.affiliation: Department of Biochemistry, University of Alberta, Edmonton, AB T6G 2H7, Canada. Electronic address: michael.schultz@ualberta.ca.
authors.forename: Michael C
authors.initials: MC
authors.lastname: Schultz
mesh_terms: D000105:Acetyl Coenzyme A / Q000378:metabolism; D000107:Acetylation; D002467:Cell Nucleus / Q000378:metabolism; D019069:Cell Respiration; D006657:Histones / Q000378:metabolism*; D008928:Mitochondria / Q000378:metabolism; D018384:Oxidative Stress; D011499:Protein Processing, Post-Translational; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*; D012441:Saccharomyces cerevisiae / Q000235:genetics / Q000254:growth & development / Q000378:metabolism*; D015398:Signal Transduction; D013997:Time Factors
chemical_list: D006657:Histones; D000105:Acetyl Coenzyme A; C071570:SNF1-related protein kinases; D017346:Protein Serine-Threonine Kinases