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


Type
Article
Change log
Authors
Bodineau, Clément 
Tomé, Mercedes 
Courtois, Sarah 
Costa, Ana SH 
Sciacovelli, Marco 
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.

Description
Keywords
AMP-Activated Protein Kinases, Adenosine Triphosphate, Animals, Antineoplastic Agents, Apoptosis, Cell Line, Tumor, Cell Proliferation, Glutamine, HCT116 Cells, HEK293 Cells, Humans, Male, Mechanistic Target of Rapamycin Complex 1, Mice, Inbred NOD, Mice, Knockout, Mice, SCID, Signal Transduction, Sirolimus, Xenograft Model Antitumor Assays
Journal Title
Nature Communications
Conference Name
Journal ISSN
2041-1723
2041-1723
Volume Title
12
Publisher
Nature Research
Sponsorship
Medical Research Council (MC_UU_12022/6)
This work was supported by funds from the following institutions: Agencia Estatal de Investigación/European Regional Development Fund, European Union (PGC2018-096244- B-I00, SAF2016-75442-R), Ministry of Science, Innovation and Universities of Spain, Spanish National Research Council—CSIC, Institut National de la Santé et de la Recherche Médicale —INSERM, Université de Bordeaux, Fondation pour la Recherche Médicale, the Conseil Régional d’Aquitaine, SIRIC-BRIO, Fondation ARC, and Institut Européen de Chimie et Biologie. C.B. was recipient of fellowships from the Minister of Higher Education, Research and Innovation (France) and the Fondation ARC (France). We thank Prof. Patricia Boya (Centro de Investigaciones Biologicas, Madrid, Spain) for kindly providing with the ATG5+/+ and ATG5−/− MEFs. We thank Prof. Benoit Viollet (Institute Cochin, Paris, France) for kindly providing with the AMPK+/+ and AMPK−/− MEFs, and the CA-AMPK plasmid.