Glutamine, MTOR and autophagy: a multiconnection relationship.

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.