1. Regulation of Autophagy by Cytosolic Acetyl-Coenzyme A
- Author
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Joseph A. Hill, Frank Madeo, Eugenia Morselli, Naoufal Zamzami, Guido Kroemer, Maria Chiara Maiuri, Mireia Niso-Santano, Federico Pietrocola, Aleksandra Andryushkova, Sabrina Schroeder, Oliver Kepp, Álvaro F. Fernández, Guillermo Mariño, Silvère Durand, Christoph Magnes, Shoaib Ahmad Malik, Tobias Pendl, Frank Sinner, David Enot, Isabelle Martins, Carlos López-Otín, Tobias Eisenberg, Patrice Codogno, Marie Scoazec, Jens S. Andersen, Alexandra Harger, Thomas R. Pieber, Chantal Bauvy, Laura Senovilla, Erika Vacchelli, Yongli Kong, Martin V. Bennetzen, Mariño, G, Pietrocola, F, Eisenberg, T, Kong, Y, Malik, Sa, Andryushkova, A, Schroeder, S, Pendl, T, Harger, A, Niso Santano, M, Zamzami, N, Scoazec, M, Durand, S, Enot, Dp, Fernández, Af, Martins, I, Kepp, O, Senovilla, L, Bauvy, C, Morselli, E, Vacchelli, E, Bennetzen, M, Magnes, C, Sinner, F, Pieber, T, López Otín, C, Maiuri, MARIA CHIARA, Codogno, P, Andersen, J, Hill, Ja, Madeo, F, and Kroemer, G.
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Cytoplasm ,Green Fluorescent Proteins ,Regulator ,Mitochondrion ,Biology ,Gene Expression Regulation, Enzymologic ,chemistry.chemical_compound ,Mice ,Adenosine Triphosphate ,Cytosol ,Acetyl Coenzyme A ,Cell Line, Tumor ,Autophagy ,Animals ,Humans ,RNA, Small Interfering ,Molecular Biology ,2. Zero hunger ,Regulation of gene expression ,Cell Nucleus ,Cell Biology ,HCT116 Cells ,Cell biology ,Mitochondria ,Mice, Inbred C57BL ,Biochemistry ,chemistry ,Microscopy, Fluorescence ,Acetylation ,Acetyltransferase ,Ketoglutaric Acids ,Adenosine triphosphate ,E1A-Associated p300 Protein ,HeLa Cells - Abstract
Acetyl-coenzyme A (AcCoA) is a major integrator of the nutritional status at the crossroads of fat, sugar, and protein catabolism. Here we show that nutrient starvation causes rapid depletion of AcCoA. AcCoA depletion entailed the commensurate reduction in the overall acetylation of cytoplasmic proteins, as well as the induction of autophagy, a homeostatic process of self-digestion. Multiple distinct manipulations designed to increase or reduce cytosolic AcCoA led to the suppression or induction of autophagy, respectively, both in cultured human cells and in mice. Moreover, maintenance of high AcCoA levels inhibited maladaptive autophagy in a model of cardiac pressure overload. Depletion of AcCoA reduced the activity of the acetyltransferase EP300, and EP300 was required for the suppression of autophagy by high AcCoA levels. Altogether, our results indicate that cytosolic AcCoA functions as a central metabolic regulator of autophagy, thus delineating AcCoA-centered pharmacological strategies that allow for the therapeutic manipulation of autophagy.
- Published
- 2014
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