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

Bodineau, Clément, Tomé, Mercedes, Courtois, Sarah, Costa, Ana SH, 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 (August 2021) Two parallel pathways connect glutamine metabolism and mTORC1 activity to regulate glutamoptosis. Nature Communications, 12 (1). p. 4814. ISSN 2041-1723

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Abstract

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.

Item Type:	Paper
Subjects:	diseases & disorders > cancer bioinformatics > genomics and proteomics > genetics & nucleic acid processing > protein structure, function, modification > protein types > mTORC1
CSHL Authors:	Costa, Ana SH
Communities:	CSHL labs > Pappin lab
SWORD Depositor:	CSHL Elements
Depositing User:	CSHL Elements
Date:	10 August 2021
Date Deposited:	18 Aug 2021 13:42
Last Modified:	01 Sep 2021 13:10
PMCID:	PMC8355106
URI:	https://repository.cshl.edu/id/eprint/40328

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