Regulation of Autophagy by Cytosolic Acetyl-Coenzyme A

• DOI: 10.1016/j.molcel.2014.01.016
• Publication Date: 2014-02-20T14:01:00Z
• Authors: Guillermo Mariño; Federico Pietrocola; Tobias Eisenberg; Yongli Kong; Shoaib Ahmad Malik; Aleksandra Andryu...; Sabrina Schroeder; Tobias Pendl; Alexandra Harger; Mireia Niso-Santano; Naoufal Zamzami; Marie Scoazec; Silvère Durand; David P. Enot; Álvaro F. Fernández; Isabelle Martins; Oliver Kepp; Laura Senovilla; Chantal Bauvy; Eugenia Morselli; Erika Vacchelli; Martin Bennetzen; Christoph Magnes; Frank Sinner; Thomas Pieber; Carlos López-Otín; Maria Chiara Maiuri; Patrice Codogno; Jens S. Andersen; Joseph A. Hill; Frank Madeo; Guido Kroemer
• Keywords: Enzymologic; 0301 basic medicine; Cytoplasm; Acetil-coenzima A; Deacetylation; Green Fluorescent Proteins; Autofagia; Inbred C57BL; Small Interfering; Fluorescence; Gene Expression Regulation, Enzymologic; Cell Line; Mice; 03 medical and health sciences; Adenosine Triphosphate; Cytosol; Acetyl Coenzyme A; Cell Line, Tumor; Autophagy; Animals; Humans; RNA, Small Interfering; Molecular Biology; 2302.21 Biología Molecular; Cell Nucleus; 2. Zero hunger; Microscopy; 0303 health sciences; Tumor; Cell Biology; HCT116 Cells; 2401.08 Genética Animal; Mitochondria; Mice, Inbred C57BL; Acetyl-coenzyme A; Gene Expression Regulation; Microscopy, Fluorescence; RNA; Ketoglutaric Acids; Deacetilación; E1A-Associated p300 Protein; HeLa Cells

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.