Acetyl-CoA carboxylase 1-dependent lipogenesis promotes autophagy downstream of AMPK.
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 (acc1 ) 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, acc1 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 acc1 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.
['Gross|Angelina S|AS|', 'Zimmermann|Andreas|A|', 'Pendl|Tobias|T|', 'Schroeder|Sabrina|S|', 'Schoenlechner|Hannes|H|', 'Knittelfelder|Oskar|O|', 'Lamplmayr|Laura|L|', 'Santiso|Ana|A|', 'Aufschnaiter|Andreas|A|', 'Waltenstorfer|Daniel|D|', 'Ortonobes Lara|Sandra|S|', 'Stryeck|Sarah|S|', 'Kast|Christina|C|', 'Ruckenstuhl|Christoph|C|', 'Hofer|Sebastian J|SJ|', 'Michelitsch|Birgit|B|', 'Woelflingseder|Martina|M|', 'Müller|Rolf|R|', 'Carmona-Gutierrez|Didac|D|', 'Madl|Tobias|T|', 'Büttner|Sabrina|S|', 'Fröhlich|Kai-Uwe|KU|', 'Shevchenko|Andrej|A|', 'Eisenberg|Tobias|T|']
D000085:Acetates D000103:Acetyl-CoA Carboxylase D001343:Autophagy D050155:Lipogenesis D018942:Macrolides D016297:Mutagenesis, Site-Directed D017346:Protein Serine-Threonine Kinases D012441:Saccharomyces cerevisiae D029701:Saccharomyces cerevisiae Proteins
lipogenesis autophagy AMPK aging acetyl-CoA carboxylase 1 Acc1 yeast Snf1 acetate oleate acetyl coenzyme A (acetyl-CoA) lipid metabolism