@article {6431, title = {Autophagy provides metabolic substrates to maintain energy charge and nucleotide pools in Ras-driven lung cancer cells.}, journal = {Genes Dev}, volume = {30}, year = {2016}, month = {2016 08 01}, pages = {1704-17}, 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.

}, keywords = {Animals, Autophagy, Autophagy-Related Protein 7, Cell Line, Tumor, Energy Metabolism, Gene Deletion, Genetic Variation, Genome, Mitochondrial, Glutamine, Lung Neoplasms, Mice, Mitochondria, Nucleosides, Nucleotides, Oxidation-Reduction, ras Proteins}, issn = {1549-5477}, doi = {10.1101/gad.283416.116}, author = {Guo, Jessie Yanxiang and Teng, Xin and Laddha, Saurabh V and Ma, Sirui and Van Nostrand, Stephen C and Yang, Yang and Khor, Sinan and Chan, Chang S and Rabinowitz, Joshua D and White, Eileen} }