Autophagy provides metabolic substrates to maintain energy charge and nucleotide pools in Ras-driven lung cancer cells

Genes Dev. 2016 Aug 1;30(15):1704-17. doi: 10.1101/gad.283416.116. Epub 2016 Aug 11.


Autophagy degrades and is thought to recycle proteins, other macromolecules, and organelles. In genetically engineered mouse models (GEMMs) for Kras-driven lung cancer, autophagy prevents the accumulation of defective mitochondria and promotes malignancy. Autophagy-deficient tumor-derived cell lines are respiration-impaired and starvation-sensitive. However, to what extent their sensitivity to starvation arises from defective mitochondria or an impaired supply of metabolic substrates remains unclear. Here, we sequenced the mitochondrial genomes of wild-type or autophagy-deficient (Atg7(-/-)) Kras-driven lung tumors. Although Atg7 deletion resulted in increased mitochondrial mutations, there were too few nonsynonymous mutations to cause generalized mitochondrial dysfunction. In contrast, pulse-chase studies with isotope-labeled nutrients revealed impaired mitochondrial substrate supply during starvation of the autophagy-deficient cells. This was associated with increased reactive oxygen species (ROS), lower energy charge, and a dramatic drop in total nucleotide pools. While starvation survival of the autophagy-deficient cells was not rescued by the general antioxidant N-acetyl-cysteine, it was fully rescued by glutamine or glutamate (both amino acids that feed the TCA cycle and nucleotide synthesis) or nucleosides. Thus, maintenance of nucleotide pools is a critical challenge for starving Kras-driven tumor cells. By providing bioenergetic and biosynthetic substrates, autophagy supports nucleotide pools and thereby starvation survival.

Keywords: ROS; Ras-driven cancer; amino acid; autophagy; energy charge; mitochondrial metabolism; nucleotide.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Autophagy*
  • Autophagy-Related Protein 7 / genetics
  • Autophagy-Related Protein 7 / metabolism
  • Cell Line, Tumor
  • Energy Metabolism / drug effects
  • Energy Metabolism / genetics
  • Gene Deletion
  • Genetic Variation
  • Genome, Mitochondrial / genetics
  • Glutamine / pharmacology
  • Lung Neoplasms / metabolism*
  • Lung Neoplasms / physiopathology
  • Mice
  • Mitochondria / metabolism
  • Nucleosides / pharmacology
  • Nucleotides / metabolism*
  • Oxidation-Reduction
  • ras Proteins / metabolism*


  • Nucleosides
  • Nucleotides
  • Glutamine
  • ras Proteins
  • Autophagy-Related Protein 7