1. Autophagy provides metabolic substrates to maintain energy charge and nucleotide pools in Ras-driven lung cancer cells
- Author
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Stephen C. Van Nostrand, Xin Teng, Jessie Yanxiang Guo, Joshua D. Rabinowitz, Eileen White, Saurabh V. Laddha, Sinan Khor, Chang S. Chan, Yang Yang, and Sirui Ma
- Subjects
0301 basic medicine ,Lung Neoplasms ,Bioenergetics ,Glutamine ,Biology ,Mitochondrion ,Autophagy-Related Protein 7 ,03 medical and health sciences ,Mice ,Cell Line, Tumor ,Genetics ,Autophagy ,Animals ,Nucleotide ,Energy charge ,chemistry.chemical_classification ,Reactive oxygen species ,Nucleotides ,Genetic Variation ,Nucleosides ,Cell biology ,Mitochondria ,Citric acid cycle ,030104 developmental biology ,chemistry ,Biochemistry ,Genome, Mitochondrial ,ras Proteins ,Energy Metabolism ,Oxidation-Reduction ,Gene Deletion ,Developmental Biology ,Research Paper - 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.
- Published
- 2016