Glutamine, MTOR and autophagy: a multiconnection relationship

Autophagy. 2022 Nov;18(11):2749-2750. doi: 10.1080/15548627.2022.2062875. Epub 2022 Apr 26.

Abstract

Cancer cells metabolize glutamine mostly through glutaminolysis, a metabolic pathway that activates MTORC1. The AMPK-MTORC1 signaling axis is a key regulator of cell growth and proliferation. Our recent investigation identified that the connection between glutamine and AMPK is not restricted to glutaminolysis. Rather, we demonstrated the crucial role of ASNS (asparagine synthetase (glutamine-hydrolyzing)) and the GABA shunt for the metabolic control of the AMPK-MTORC1 axis during glutamine sufficiency. Our results elucidated a metabolic network by which glutamine metabolism regulates the MTORC1-macroautophagy/autophagy pathway through two independent branches involving glutaminolysis and ASNS-GABA shunt.Abbreviations: αKG: alpha-ketoglutarate; AMPK: AMP-activated protein kinase; ASNS: asparagine synthetase (glutamine-hydrolyzing); GLUD/GDH: glutamate dehydrogenase; GLS: glutaminase; GOT1: glutamic-oxaloacetic transaminase 1; MTORC1: mechanistic target of rapamycin kinase complex 1; TCA: tricarboxylic acid.

Keywords: ASNS; GABA-shunt; MTORC1; glutamine; glutamoptosis.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • AMP-Activated Protein Kinases
  • Autophagy*
  • Glutamine* / metabolism
  • Mechanistic Target of Rapamycin Complex 1 / metabolism
  • gamma-Aminobutyric Acid

Substances

  • Glutamine
  • AMP-Activated Protein Kinases
  • Mechanistic Target of Rapamycin Complex 1
  • gamma-Aminobutyric Acid

Grants and funding

This work was supported by the Agencia Estatal de Investigación [PGC2018-096244- B-I00, SAF2016-75442-R];Ministry of Science, Innovation and Universities of Spain, Spanish National Research Council—CSIC;