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

作者：Eisenberg Tobias; Schroeder Sabrina; Andryushkova Aleksandra; Pendl Tobias; Kuettner Victoria; Bhukel Anuradha; Marino Guillermo; Pietrocola Federico; Harger Alexandra; Zimmermann Andreas; Moustafa Tarek; Sprenger Adrian; Jany Evelyne; Buettner 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

来源：Cell Metabolism, 2014, 19(3): 431-444.

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-coenzymeA(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.

• 出版日期2014-3-4