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Cell Rep. 2014 Apr 24;7(2):565-74. doi: 10.1016/j.celrep.2014.03.029. Epub 2014 Apr 13.

Rewiring AMPK and mitochondrial retrograde signaling for metabolic control of aging and histone acetylation in respiratory-defective cells.

Author information

1
Department of Biochemistry, University of Alberta, Edmonton, AB T6G 2H7, Canada.
2
Department of Chemistry, University of Alberta, Edmonton, AB T6G 2H7, Canada.
3
Department of Biochemistry, University of Alberta, Edmonton, AB T6G 2H7, Canada. Electronic address: michael.schultz@ualberta.ca.

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.

PMID:
24726357
DOI:
10.1016/j.celrep.2014.03.029
[Indexed for MEDLINE]
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