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Updated: Jan 24, 2026

Techniques to Induce and Quantify Cellular Senescence
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Techniques to Induce and Quantify Cellular Senescence

Published on: May 1, 2017

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Blockage of glutamine-dependent anaplerosis affects mTORC1/2 activity and ultimately leads to cellular

Geng-You Liao1,2, Ming-Ting Lee3, Jhen-Jia Fan1

  • 1Institute of Molecular and Cellular Biology, College of Life Science, National Taiwan University, Taipei 106, Taiwan.

Biology Open
|May 18, 2019
PubMed

Insights

Glutamine-dependent anaplerosis fuels cell growth by activating mTORC1 and inhibiting senescence. Blocking this process with amino-oxyacetate (AOA) triggers cell cycle arrest and senescence, which can be reversed by anaplerotic factors.

Area of Science:

  • Cell Biology
  • Metabolic Regulation

Background:

  • Cellular senescence is a state of irreversible growth arrest.
  • Glutamine metabolism plays a critical role in cellular processes, including proliferation and survival.
  • Anaplerosis replenishes the TCA cycle intermediates, impacting cellular metabolism.

Purpose of the Study:

  • To investigate the role of glutamine-dependent anaplerosis in regulating cell fate, specifically proliferation and senescence.
  • To elucidate the underlying molecular mechanisms, including mTOR signaling and cell cycle control.
  • To determine the involvement of p16INK4A in mediating the effects of anaplerosis inhibition on senescence.

Main Methods:

  • Utilized WI38 normal human embryonic fibroblast and U2OS human osteosarcoma cell lines.
  • Employed amino-oxyacetate (AOA), a pharmacological inhibitor of glutamine-dependent anaplerosis.
  • Assessed cell proliferation, cell cycle arrest, and senescence markers (p53, p21CIP1, p16INK4A, Rb).
  • Investigated the impact of anaplerotic factors (α-ketoglutarate, pyruvate, oxaloacetate) and ROS scavenger (NAC) on AOA-induced effects.

Main Results:

  • AOA induced mTORC1 inactivation and mTORC2 activation, leading to cell cycle arrest and senescence in WI38 cells.
  • These effects were reversed by anaplerotic factors but not by NAC.
  • AOA-induced senescence involved increased p53, p21CIP1, p16INK4A, and decreased Rb protein levels.
  • In p16INK4A-deficient or -knockdown cells, AOA still affected proliferation and Rb phosphorylation but senescence induction was altered, suggesting a role for p16INK4A.

Conclusions:

  • Glutamine-dependent anaplerosis is essential for cell growth, linked to mTORC1 activation and mTORC2 inactivation.
  • Inhibition of anaplerosis promotes cellular senescence, particularly in a p16INK4A-dependent manner.
  • Restoring anaplerotic intermediates can counteract the pro-senescence effects of anaplerosis inhibition.
Keywords:
Amino-oxyacetateCellular senescenceGlutamine-dependent anaplerosisMetabolismmTORCp16INK4A

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