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Two parallel pathways connect glutamine metabolism and mTORC1 activity to regulate glutamoptosis
Clément Bodineau1,2, Mercedes Tomé1, Sarah Courtois3
1Centro Andaluz de Biología Molecular y Medicina Regenerativa-CABIMER, Consejo Superior de Investigaciones Científicas, Universidad de Sevilla, Universidad Pablo de Olavide, Seville, Spain.
Nature Communications
|August 11, 2021
Summary
AMPK reactivation inhibits glutamoptosis, a form of cell death linked to glutaminolysis and mTORC1 signaling. Glutamine metabolism connects to mTORC1 via two pathways, impacting cancer cell growth.
Area of Science:
- Cellular biology
- Metabolic pathways
- Cancer research
Background:
- Glutamoptosis, a cell death pathway, is triggered by aberrant glutaminolysis and mTORC1 signaling during nutritional stress in proliferating cells.
- The role of the energy sensor AMPK in glutamoptosis remains undefined.
Purpose of the Study:
- To investigate the role of AMPK in regulating glutamoptosis.
- To elucidate the metabolic connections between glutamine, mTORC1, and AMPK.
Main Methods:
- In vitro and in vivo experiments were conducted.
- Cellular signaling pathways and metabolic flux were analyzed.
- The impact of AMPK activation on glutaminolysis and cell death was assessed.
Main Results:
- AMPK reactivation was found to inhibit both mTORC1 activation and glutamoptosis.
- Glutamine metabolism was shown to support ATP production and AMPK inhibition via asparagine synthesis and the GABA shunt, independent of glutaminolysis.
- Two distinct pathways linking glutamine metabolism to mTORC1 activation were identified: an alpha-ketoglutarate-dependent pathway and an ATP/AMPK-dependent pathway.
Conclusions:
- AMPK plays a critical role in preventing glutamoptosis by modulating glutamine metabolism and mTORC1 signaling.
- The dual metabolic regulation of mTORC1 by glutamine highlights the complexity of cellular energy homeostasis.
- Understanding these pathways is crucial for developing targeted therapies against cancer.
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