Acetyl-CoA carboxylase 1-dependent lipogenesis promotes autophagy downstream of AMPK.

First Authors Angelina S Gross
Authors Angelina S Gross, Andreas Zimmermann, Tobias Pendl, Sabrina Schroeder, Hannes Schoenlechner, Oskar Knittelfelder, Laura Lamplmayr, Ana Santiso, Andreas Aufschnaiter, Daniel Waltenstorfer, Sandra Ortonobes Lara, Sarah Stryeck, Christina Kast, Christoph Ruckenstuhl, Sebastian J Hofer, Birgit Michelitsch, Martina Woelflingseder, Rolf Müller, Didac Carmona-Gutierrez, Tobias Madl, Sabrina Büttner, Kai-Uwe Fröhlich, Andrej Shevchenko, Tobias Eisenberg
Corresponding Authors
Last Authors Tobias Eisenberg
Journal Name The Journal of biological chemistry (J Biol Chem)
Volume 294
Issue 32
Page Range 12020-12039
PubMed ID 31209110
WebOfScience Link WOS:000484284500008
Open Access false
Print Publication Date 2019-08-09
Online Publication Date
Abstract Autophagy, a membrane-dependent catabolic process, ensures survival of aging cells and depends on the cellular energetic status. Acetyl-CoA carboxylase 1 (Acc1) connects central energy metabolism to lipid biosynthesis and is rate-limiting for the de novo synthesis of lipids. However, it is unclear how de novo lipogenesis and its metabolic consequences affect autophagic activity. Here, we show that in aging yeast, autophagy levels highly depend on the activity of Acc1. Constitutively active Acc1 (acc1S/A ) or a deletion of the Acc1 negative regulator, Snf1 (yeast AMPK), shows elevated autophagy levels, which can be reversed by the Acc1 inhibitor soraphen A. Vice versa, pharmacological inhibition of Acc1 drastically reduces cell survival and results in the accumulation of Atg8-positive structures at the vacuolar membrane, suggesting late defects in the autophagic cascade. As expected, acc1S/A cells exhibit a reduction in acetate/acetyl-CoA availability along with elevated cellular lipid content. However, concomitant administration of acetate fails to fully revert the increase in autophagy exerted by acc1S/A Instead, administration of oleate, while mimicking constitutively active Acc1 in WT cells, alleviates the vacuolar fusion defects induced by Acc1 inhibition. Our results argue for a largely lipid-dependent process of autophagy regulation downstream of Acc1. We present a versatile genetic model to investigate the complex relationship between acetate metabolism, lipid homeostasis, and autophagy and propose Acc1-dependent lipogenesis as a fundamental metabolic path downstream of Snf1 to maintain autophagy and survival during cellular aging.
Cover Image
Affiliated With Postdocs, Shevchenko
Selected By
Acknowledged Services
Publication Status Published
Edoc Link
Sfx Link
DOI 10.1074/jbc.RA118.007020
Display Publisher Download Only false
Visible On MPI-CBG Website true
PDF Downloadable true
Created By thuem
Added Date 2019-07-30
Last Edited By verhegge
Last Edited Date 2019-09-24 13:00:29.647
Library ID 7439
Document ID
Entry Complete true
eDoc Compliant true
Include in Edoc Report true
Author Affiliations Complete false