Nucleocytosolic depletion of the energy metabolite acetyl-coenzyme a stimulates autophagy and prolongs lifespan.

Eisenberg, Tobias and Schroeder, Sabrina and Andryushkova, Aleksandra and Pendl, Tobias and Küttner, Victoria and Bhukel, Anuradha and Mariño, Guillermo and Pietrocola, Federico and Harger, Alexandra and Zimmermann, Andreas and Moustafa, Tarek and Sprenger, Adrian and Jany, Evelyne and Büttner, Sabrina and Carmona-Gutierrez, Didac and Ruckenstuhl, Christoph and Ring, Julia and Reichelt, Wieland and Schimmel, Katharina and Leeb, Tina and Moser, Claudia and Schatz, Stefanie and Kamolz, Lars-Peter and Magnes, Christoph and Sinner, Frank and Sedej, Simon and Fröhlich, Kai-Uwe and Juhasz, Gabor and Pieber, Thomas R and Dengjel, Jörn and Sigrist, Stephan J and Kroemer, Guido and Madeo, Frank (2014) Nucleocytosolic depletion of the energy metabolite acetyl-coenzyme a stimulates autophagy and prolongs lifespan. Cell metabolism, 19 (3). pp. 431-44. ISSN 1932-7420

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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.

Item Type: Article
Subjects: Q Science / természettudomány > Q1 Science (General) / természettudomány általában
Depositing User: Dr. Gabor Juhasz
Date Deposited: 18 Sep 2014 13:39
Last Modified: 18 Sep 2014 13:39

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