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  3. Redefining the role of AMPK in autophagy and the energy stress response

Redefining the role of AMPK in autophagy and the energy stress response

  • Nat Commun. 2023 May 24;14(1):2994. doi: 10.1038/s41467-023-38401-z.
Ji-Man Park 1,  Da-Hye Lee 1,  Do-Hyung Kim 2 3 4 5
Affiliations

Affiliations

  • 1 Department of Biochemistry, Molecular Biology and Biophysics, University of Minnesota, Minneapolis, MN, 55455, USA.
  • 2 Department of Biochemistry, Molecular Biology and Biophysics, University of Minnesota, Minneapolis, MN, 55455, USA. dhkim@umn.edu.
  • 3 Institute for Diabetes, Obesity and Metabolism, University of Minnesota, Minneapolis, MN, 55455, USA. dhkim@umn.edu.
  • 4 Center for Immunology, University of Minnesota, Minneapolis, MN, 55455, USA. dhkim@umn.edu.
  • 5 Masonic Cancer Center, University of Minnesota, Minneapolis, MN, 55455, USA. dhkim@umn.edu.
PMID: 37225695 DOI: 10.1038/s41467-023-38401-z
Abstract

Autophagy maintains cellular homeostasis during low energy states. According to the current understanding, glucose-depleted cells induce Autophagy through AMPK, the primary energy-sensing kinase, to acquire energy for survival. However, contrary to the prevailing concept, our study demonstrates that AMPK inhibits ULK1, the kinase responsible for Autophagy initiation, thereby suppressing Autophagy. We found that glucose starvation suppresses amino acid starvation-induced stimulation of ULK1-Atg14-Vps34 signaling via AMPK activation. During an energy crisis caused by mitochondrial dysfunction, the LKB1-AMPK axis inhibits ULK1 activation and Autophagy induction, even under amino acid starvation. Despite its inhibitory effect, AMPK protects the ULK1-associated Autophagy machinery from caspase-mediated degradation during energy deficiency, preserving the cellular ability to initiate Autophagy and restore homeostasis once the stress subsides. Our findings reveal that dual functions of AMPK, restraining abrupt induction of Autophagy upon energy shortage while preserving essential Autophagy components, are crucial to maintain cellular homeostasis and survival during energy stress.

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