Skip to main content

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

Author(s): Guo, Jessie Yanxiang; Teng, Xin; Laddha, Saurabh V.; Ma, Sirui; Van Nostrand, Stephen C.; et al

To refer to this page use:
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.
Publication Date: 1-Aug-2016
Electronic Publication Date: 11-Aug-2016
Citation: Guo, Jessie Yanxiang, Teng, Xin, Laddha, Saurabh V, Ma, Sirui, Van Nostrand, Stephen C., Yang, Yang, Khor, Sinan, Chan, Chang S., Rabinowitz, Joshua D., White, Eileen. (2016). Autophagy provides metabolic substrates to maintain energy charge and nucleotide pools in Ras-driven lung cancer cells. Genes & Development, 30 (15), 1704 - 1717. doi:10.1101/gad.283416.116
DOI: doi:10.1101/gad.283416.116
ISSN: 0890-9369
EISSN: 1549-5477
Pages: 1704 - 1717
Type of Material: Journal Article
Journal/Proceeding Title: Genes & Development
Version: Final published version. Article is made available in OAR by the publisher's permission or policy.
Notes: Supplemental Material

Items in OAR@Princeton are protected by copyright, with all rights reserved, unless otherwise indicated.