Nucleocytosolic Depletion of the Energy Metabolite Acetyl-Coenzyme A Stimulates Autophagy and Prolongs Lifespan

• Published in: Cell metabolism Vol. 19; no. 3; pp. 431 - 444
• Main Authors: Eisenberg, Tobias, Schroeder, Sabrina, Andryushkova, Aleksandra, Pendl, Tobias, Küttner, Victoria, Bhukel, Anuradha, Mariño, Guillermo, Pietrocola, Federico, Harger, Alexandra, Zimmermann, Andreas, Moustafa, Tarek, Sprenger, Adrian, Jany, Evelyne, Büttner, Sabrina, Carmona-Gutierrez, Didac, Ruckenstuhl, Christoph, Ring, Julia, Reichelt, Wieland, Schimmel, Katharina, Leeb, Tina, Moser, Claudia, Schatz, Stefanie, Kamolz, Lars-Peter, Magnes, Christoph, Sinner, Frank, Sedej, Simon, Fröhlich, Kai-Uwe, Juhasz, Gabor, Pieber, Thomas R., Dengjel, Jörn, Sigrist, Stephan J., Kroemer, Guido, Madeo, Frank
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 04.03.2014; Elsevier; Cell Press
• Subjects: Acetyl Coenzyme A - biosynthesis; Acetylation; Aging; Animals; Autophagy; Autophagy-Related Protein 7; Coenzyme A Ligases - antagonists & inhibitors; Coenzyme A Ligases - genetics; Coenzyme A Ligases - metabolism; Drosophila - enzymology; Drosophila Proteins - antagonists & inhibitors; Drosophila Proteins - genetics; Drosophila Proteins - metabolism; Energy Metabolism; Histones - metabolism; Life Sciences; Longevity; Membrane Proteins - deficiency; Membrane Proteins - genetics; Membrane Proteins - metabolism; Mitochondria - metabolism; Phosphotransferases (Alcohol Group Acceptor) - deficiency; Phosphotransferases (Alcohol Group Acceptor) - genetics; Phosphotransferases (Alcohol Group Acceptor) - metabolism; Saccharomyces cerevisiae - metabolism; Saccharomyces cerevisiae Proteins - antagonists & inhibitors; Saccharomyces cerevisiae Proteins - genetics; Saccharomyces cerevisiae Proteins - metabolism; Up-Regulation
• ISSN: 1550-4131; 1932-7420; 1932-7420
• DOI: 10.1016/j.cmet.2014.02.010

Healthy aging depends on removal of damaged cellular material that is in part mediated by autophagy. The nutritional status of cells affects both aging and autophagy through as-yet-elusive metabolic circuitries. Here, we show that nucleocytosolic acetyl-coenzyme A (AcCoA) production is a metabolic repressor of autophagy during aging in yeast. Blocking the mitochondrial route to AcCoA by deletion of the CoA-transferase ACH1 caused cytosolic accumulation of the AcCoA precursor acetate. This led to hyperactivation of nucleocytosolic AcCoA-synthetase Acs2p, triggering histone acetylation, repression of autophagy genes, and an age-dependent defect in autophagic flux, culminating in a reduced lifespan. Inhibition of nutrient signaling failed to restore, while simultaneous knockdown of ACS2 reinstated, autophagy and survival of ach1 mutant. Brain-specific knockdown of Drosophila AcCoA synthetase was sufficient to enhance autophagic protein clearance and prolong lifespan. Since AcCoA integrates various nutrition pathways, our findings may explain diet-dependent lifespan and autophagy regulation. [Display omitted] •Acetyl-CoA (AcCoA) metabolism regulates autophagy during aging•Autophagy regulation by AcCoA metabolism acts downstream of nutrient signaling•Brain-specific knockdown of Drosophila AcCoA synthetase prolongs lifespan•Histone point mutations permanently activate autophagy during aging Autophagy plays a crucial role in healthy aging. By blocking mitochondrial AcCoA production, Eisenberg et al. show that accumulation of nucleocytosolic AcCoA inhibits autophagy and reduces lifespan through a conserved epigenetic mechanism involving histone acetylation of specific autophagy genes in yeast and flies.