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

Cell metabolism, 2014-03, Vol.19 (3), p.431-444 [Peer Reviewed Journal]

2014 The Authors ;Copyright © 2014 The Authors. Published by Elsevier Inc. All rights reserved. ;2014 The Authors 2014 ;ISSN: 1550-4131 ;EISSN: 1932-7420 ;DOI: 10.1016/j.cmet.2014.02.010 ;PMID: 24606900

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Title:
Nucleocytosolic Depletion of the Energy Metabolite Acetyl-Coenzyme A Stimulates Autophagy and Prolongs Lifespan
Author: 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
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 ; 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
Is Part Of: Cell metabolism, 2014-03, Vol.19 (3), p.431-444
Description: 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.
Publisher: United States: Elsevier Inc
Language: English
Identifier: ISSN: 1550-4131
EISSN: 1932-7420
DOI: 10.1016/j.cmet.2014.02.010
PMID: 24606900
Source: Cell Press Free Archives
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Nucleocytosolic Depletion of the Energy Metabolite Acetyl-Coenzyme A Stimulates Autophagy and Prolongs Lifespan

2014 The Authors ;Copyright © 2014 The Authors. Published by Elsevier Inc. All rights reserved. ;2014 The Authors 2014 ;ISSN: 1550-4131 ;EISSN: 1932-7420 ;DOI: 10.1016/j.cmet.2014.02.010 ;PMID: 24606900

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