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

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• 作者：Tobias Eisenberg¹ ; ¹⁷ ; Sabrina Schroeder¹ ; ¹⁷ ; Aleksandra Andryushkova¹ ; ¹⁷ ; Tobias Pendl¹ ; Victoria Kü ; ttner² ; ³ ; Anuradha Bhukel⁴ ; ⁵ ; Guillermo Mariñ ; o⁶ ; ⁷ ; ⁸ ; Federico Pietrocola⁶ ; ⁷ ; ⁸ ; Alexandra Harger¹ ; ⁹ ; Andreas Zimmermann¹ ; Tarek Moustafa¹ ; Adrian Sprenger² ; ³ ; Evelyne Jany¹ ; Sabrina Bü ; ttner¹ ; Didac Carmona-Gutierrez¹ ; Christoph Ruckenstuhl¹ ; Julia Ring¹ ; Wieland Reichelt¹ ; Katharina Schimmel¹ ; Tina Leeb¹ ; Claudia Moser¹ ; Stefanie Schatz¹ ; Lars-Peter Kamolz¹⁰ ; Christoph Magnes¹¹ ; Frank Sinner⁹ ; ¹¹ ; Simon Sedej¹² ; Kai-Uwe Frö ; hlich¹ ; Gabor Juhasz¹³ ; Thomas R. Pieber⁹ ; ¹¹ ; Jö ; rn Dengjel² ; ³ ; Stephan J. Sigrist⁴ ; ⁵ ; Guido Kroemer⁶ ; ⁷ ; ⁸ ; ¹⁴ ; ¹⁵ ; ¹⁶ ; ¹⁸ ; ^{kroemer@orange.fr" class="auth_mail} ; Frank Madeo¹ ; ¹⁸ ; ^{frank.madeo@uni-graz.at" class="auth_mail}
• 刊名：Cell Metabolism
• 出版年：4 March, 2014
• 年：2014
• 卷：19
• 期：3
• 页码：431-444
• 全文大小：3798 K

文摘

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Summary

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聽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.