Glucose addiction of TSC null cells is caused by failed mTORC1-dependent balancing of metabolic demand with supply.
The mTORC1-signaling pathway integrates environmental conditions into distinct signals for cell growth by balancing anabolic and catabolic processes. Accordingly, energetic stress inhibits mTORC1 signaling predominantly through AMPK-dependent activation of TSC1/2. Thus, TSC1/2-/- cells are hypersensitive to glucose deprivation, and this has been linked to increased p53 translation and activation of apoptosis. Herein, we show that mTORC1 inhibition during glucose deprivation prevented not only the execution of death, but also induction of energetic stress. mTORC1 inhibition during glucose deprivation decreased AMPK activation and allowed ATP to remain high, which was both necessary and sufficient for protection. This effect was not due to increased catabolic activities such as autophagy, but rather exclusively due to decreased anabolic processes, reducing energy consumption. Specifically, TSC1/2-/- cells become highly dependent on glutamate dehydrogenase-dependent glutamine metabolism via the TCA cycle for survival. Therefore, mTORC1 inhibition during energetic stress is primarily to balance metabolic demand with supply.
Department of Cell Biology, Harvard Medical School, Boston, MA 02115, USA.
Andrew Y
AY
Choo
Sang Gyun
SG
Kim
Matthew G
MG
Vander Heiden
Sarah J
SJ
Mahoney
Hieu
H
Vu
Sang-Oh
SO
Yoon
Lewis C
LC
Cantley
John
J
Blenis
D000091162:AMP-Activated Protein Kinase Kinases; D000818:Animals; D002478:Cells, Cultured; D005947:Glucose / Q000378:metabolism*; D011494:Protein Kinases / Q000378:metabolism; D051381:Rats; D015398:Signal Transduction; D014157:Transcription Factors / Q000378:metabolism*; D000077004:Tuberous Sclerosis Complex 1 Protein; D000077005:Tuberous Sclerosis Complex 2 Protein; D025521:Tumor Suppressor Proteins / Q000172:deficiency* / Q000378:metabolism
C519510:Crtc1 protein, rat; D014157:Transcription Factors; C000624652:Tsc1 protein, rat; D000077004:Tuberous Sclerosis Complex 1 Protein; D000077005:Tuberous Sclerosis Complex 2 Protein; D025521:Tumor Suppressor Proteins; D011494:Protein Kinases; D000091162:AMP-Activated Protein Kinase Kinases; D005947:Glucose