Asparagine couples mitochondrial respiration to ATF4 activity and tumor growth

Cell Metab. 2021 May 4;33(5):1013-1026.e6. doi: 10.1016/j.cmet.2021.02.001. Epub 2021 Feb 19.


Mitochondrial respiration is critical for cell proliferation. In addition to producing ATP, respiration generates biosynthetic precursors, such as aspartate, an essential substrate for nucleotide synthesis. Here, we show that in addition to depleting intracellular aspartate, electron transport chain (ETC) inhibition depletes aspartate-derived asparagine, increases ATF4 levels, and impairs mTOR complex I (mTORC1) activity. Exogenous asparagine restores proliferation, ATF4 and mTORC1 activities, and mTORC1-dependent nucleotide synthesis in the context of ETC inhibition, suggesting that asparagine communicates active respiration to ATF4 and mTORC1. Finally, we show that combination of the ETC inhibitor metformin, which limits tumor asparagine synthesis, and either asparaginase or dietary asparagine restriction, which limit tumor asparagine consumption, effectively impairs tumor growth in multiple mouse models of cancer. Because environmental asparagine is sufficient to restore tumor growth in the context of respiration impairment, our findings suggest that asparagine synthesis is a fundamental purpose of tumor mitochondrial respiration, which can be harnessed for therapeutic benefit to cancer patients.

Keywords: asparaginase; asparagine; cancer metabolism; cancer treatment; dietary restriction; metformin; respiration.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Activating Transcription Factor 4 / metabolism*
  • Animals
  • Asparagine / metabolism*
  • Asparagine / pharmacology
  • Aspartic Acid / deficiency
  • Aspartic Acid / pharmacology
  • Cell Line, Tumor
  • Cell Proliferation / drug effects
  • Diet / veterinary
  • Electron Transport Chain Complex Proteins / antagonists & inhibitors
  • Electron Transport Chain Complex Proteins / metabolism
  • Humans
  • Mechanistic Target of Rapamycin Complex 1 / metabolism
  • Metformin / pharmacology
  • Metformin / therapeutic use
  • Mice
  • Mice, Inbred NOD
  • Mitochondria / drug effects
  • Mitochondria / metabolism*
  • Neoplasms / drug therapy
  • Neoplasms / mortality
  • Neoplasms / pathology
  • Nucleotides / metabolism
  • Survival Rate


  • Electron Transport Chain Complex Proteins
  • Nucleotides
  • Activating Transcription Factor 4
  • Aspartic Acid
  • Asparagine
  • Metformin
  • Mechanistic Target of Rapamycin Complex 1