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Autophagy provides metabolic substrates to maintain energy charge and nucleotide pools in Ras-driven lung cancer cells
- Source :
- Genesdevelopment. 30(15)
- Publication Year :
- 2016
-
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.
- 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
Subjects
Details
- ISSN :
- 15495477
- Volume :
- 30
- Issue :
- 15
- Database :
- OpenAIRE
- Journal :
- Genesdevelopment
- Accession number :
- edsair.doi.dedup.....daa0a8f8f12f198a7057dcea57e5c674