Glucose Addiction of TSC Null Cells Is Caused by Failed mTORC1-Dependent Balancing of Metabolic Demand with Supply Academic Article uri icon

Overview

MeSH Major

  • Glucose
  • Transcription Factors
  • Tumor Suppressor Proteins

abstract

  • 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.

publication date

  • May 28, 2010

Research

keywords

  • Academic Article

Identity

Language

  • eng

PubMed Central ID

  • PMC2896794

Digital Object Identifier (DOI)

  • 10.1016/j.molcel.2010.05.007

PubMed ID

  • 20513425

Additional Document Info

start page

  • 487

end page

  • 99

volume

  • 38

number

  • 4