Two parallel pathways connect glutamine metabolism and mTORC1 activity to regulate glutamoptosis

• Published in: Nature communications Vol. 12; no. 1; pp. 4814 - 13
• Main Authors: Bodineau, Clément, Tomé, Mercedes, Courtois, Sarah, Costa, Ana S. H., Sciacovelli, Marco, Rousseau, Benoit, Richard, Elodie, Vacher, Pierre, Parejo-Pérez, Carlos, Bessede, Emilie, Varon, Christine, Soubeyran, Pierre, Frezza, Christian, Murdoch, Piedad del Socorro, Villar, Victor H., Durán, Raúl V.
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 10.08.2021; Nature Publishing Group; Nature Portfolio
• Subjects: 13; 14; 14/19; 631/45/320; 631/80/82/23; 631/80/86/2369; 64; 64/60; 82/51; 96; 96/106; 96/2; 96/31; Adenosine Triphosphate - metabolism; Amino acids; AMP-Activated Protein Kinases - metabolism; Animals; Antineoplastic Agents - pharmacology; Apoptosis; Apoptosis - physiology; Asparagine; ATP; Bioenergetics; Cancer; Cell death; Cell Line, Tumor; Cell Proliferation - physiology; Glutamine; Glutamine - metabolism; HCT116 Cells; HEK293 Cells; Humanities and Social Sciences; Humans; Ketoglutaric acid; Male; Mechanistic Target of Rapamycin Complex 1 - metabolism; Metabolism; Mice; Mice, Inbred NOD; Mice, Knockout; Mice, SCID; multidisciplinary; Science; Science (multidisciplinary); Signal Transduction - physiology; Sirolimus - analogs & derivatives; Sirolimus - pharmacology; Xenograft Model Antitumor Assays - methods; γ-Aminobutyric acid
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-021-25079-4

Glutamoptosis is the induction of apoptotic cell death as a consequence of the aberrant activation of glutaminolysis and mTORC1 signaling during nutritional imbalance in proliferating cells. The role of the bioenergetic sensor AMPK during glutamoptosis is not defined yet. Here, we show that AMPK reactivation blocks both the glutamine-dependent activation of mTORC1 and glutamoptosis in vitro and in vivo. We also show that glutamine is used for asparagine synthesis and the GABA shunt to produce ATP and to inhibit AMPK, independently of glutaminolysis. Overall, our results indicate that glutamine metabolism is connected with mTORC1 activation through two parallel pathways: an acute alpha-ketoglutarate-dependent pathway; and a secondary ATP/AMPK-dependent pathway. This dual metabolic connection between glutamine and mTORC1 must be considered for the future design of therapeutic strategies to prevent cell growth in diseases such as cancer. The metabolism of amino acids and the cellular energy sensor AMPK are both connected to mTORC1, but the pathway details have not been well defined. Here, the authors show that glutamine metabolism and mTORC1 have two regulatory connections with relevance to cancer therapeutics design.