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

Yanxiang Guo, Xin Teng, Saurabh V. Laddha, Sirui Ma, Stephen C. Van Nostrand, Yang Yang, Sinan Khor, Chang Chan, Joshua D. Rabinowitz, Eileen White

Research output: Contribution to journalArticle

105 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)1704-1717
Number of pages14
JournalGenes and Development
Volume30
Issue number15
DOIs
StatePublished - Aug 1 2016

All Science Journal Classification (ASJC) codes

  • Genetics
  • Developmental Biology

Keywords

  • Amino acid
  • Autophagy
  • Energy charge
  • Mitochondrial metabolism
  • Nucleotide
  • ROS
  • Ras-driven cancer

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    Guo, Y., Teng, X., Laddha, S. V., Ma, S., Van Nostrand, S. C., Yang, Y., Khor, S., Chan, C., Rabinowitz, J. D., & White, E. (2016). Autophagy provides metabolic substrates to maintain energy charge and nucleotide pools in Ras-driven lung cancer cells. Genes and Development, 30(15), 1704-1717. https://doi.org/10.1101/gad.283416.116