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J Biol Chem. 2019 Aug 9;294(32):12020-12039. doi: 10.1074/jbc.RA118.007020. Epub 2019 Jun 17.

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

Author information

1
Institute of Molecular Biosciences, NAWI Graz, University of Graz, 8010 Graz, Austria.
2
Central Lab Gracia, NAWI Graz, University of Graz, 8010 Graz, Austria.
3
BioTechMed-Graz, 8010 Graz, Austria.
4
Max Planck Institute of Molecular Cell Biology and Genetics, 01307 Dresden, Germany.
5
Department of Molecular Biosciences, Wenner-Gren Institute, Stockholm University, 114 19 Stockholm, Sweden.
6
Gottfried Schatz Research Center for Cell Signaling, Metabolism, and Aging, Institute of Molecular Biology and Biochemistry, Medical University of Graz, 8036 Graz, Austria.
7
Division of Plastic, Aesthetic, and Reconstructive Surgery, Department of Surgery, Medical University of Graz, 8036 Graz, Austria.
8
Helmholtz Institute for Pharmaceutical Research Saarland, 66123 Saarbrücken, Germany.
9
Institute of Molecular Biosciences, NAWI Graz, University of Graz, 8010 Graz, Austria tobias.eisenberg@uni-graz.at.

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.

KEYWORDS:

AMPK; Acc1; Snf1; acetate; acetyl coenzyme A (acetyl-CoA); acetyl-CoA carboxylase 1; aging; autophagy; lipid metabolism; lipogenesis; oleate; yeast

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