Dataset Information

DDIT3 Directs a Dual Mechanism to Balance Glycolysis and Oxidative Phosphorylation during Glutamine Deprivation.

ABSTRACT: Extracellular glutamine represents an important energy source for many cancer cells and its metabolism is intimately involved in maintaining redox homeostasis. The heightened metabolic activity within tumor tissues can result in glutamine deficiency, necessitating metabolic reprogramming responses. Here, dual mechanisms involving the stress-responsive transcription factor DDIT3 (DNA damage induced transcript 3) that establishes an interrelationship between glycolysis and mitochondrial respiration are revealed. DDIT3 is induced during glutamine deprivation to promote glycolysis and adenosine triphosphate production via suppression of the negative glycolytic regulator TIGAR. In concert, a proportion of the DDIT3 pool translocates to the mitochondria and suppresses oxidative phosphorylation through LONP1-mediated down-regulation of COQ9 and COX4. This in turn dampens the sustained levels of reactive oxygen species that follow glutamine withdrawal. Together these mechanisms constitute an adaptive survival mechanism permitting tumor cells to survive metabolic stress induced by glutamine starvation.

SUBMITTER: Li M

PROVIDER: S-EPMC8188220 | biostudies-literature | 2021 Jun

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

DDIT3 Directs a Dual Mechanism to Balance Glycolysis and Oxidative Phosphorylation during Glutamine Deprivation.

Li Mingyue M Thorne Rick Francis RF Shi Ronghua R Zhang Xu Dong XD Li Jingmin J Li Jingtong J Zhang Qingyuan Q Wu Mian M Liu Lianxin L

Advanced science (Weinheim, Baden-Wurttemberg, Germany) 20210327 11

Extracellular glutamine represents an important energy source for many cancer cells and its metabolism is intimately involved in maintaining redox homeostasis. The heightened metabolic activity within tumor tissues can result in glutamine deficiency, necessitating metabolic reprogramming responses. Here, dual mechanisms involving the stress-responsive transcription factor DDIT3 (DNA damage induced transcript 3) that establishes an interrelationship between glycolysis and mitochondrial respiratio ...[more]

PMID: 34105294

Similar Datasets

Project description:BackgroundTumourigenic cells modify metabolic pathways in order to facilitate increased proliferation and cell survival resulting in glucose- and glutamine addiction. Previous research indicated that glutamine deprivation resulted in potential differential activity targeting tumourigenic cells more prominently. This is ascribed to tumourigenic cells utilising increased glutamine quantities for enhanced glycolysis- and glutaminolysis. In this study, the effects exerted by glutamine deprivation on reactive oxygen species (ROS) production, mitochondrial membrane potential, cell proliferation and cell death in breast tumourigenic cell lines (MCF-7, MDA-MB-231, BT-20) and a non-tumourigenic breast cell line (MCF-10A) were investigated.ResultsSpectrophotometry demonstrated that glutamine deprivation resulted in decreased cell growth in a time-dependent manner. MCF-7 cell growth was decreased to 61% after 96 h of glutamine deprivation; MDA-MB-231 cell growth was decreased to 78% cell growth after 96 h of glutamine deprivation, MCF-10A cell growth was decreased 89% after 96 h of glutamine deprivation and BT-20 cell growth decreased to 86% after 24 h of glutamine deprivation and remained unchanged until 96 h of glutamine deprivation. Glutamine deprivation resulted in oxidative stress where superoxide levels were significantly elevated after 96 h in the MCF-7- and MDA-MB-231 cell lines. Time-dependent production of hydrogen peroxide was accompanied by aberrant mitochondrial membrane potential. The effects of ROS and mitochondrial membrane potential were more prominently observed in the MCF-7 cell line when compared to the MDA-MB-231-, MCF-10A- and BT-20 cell lines. Cell cycle progression revealed that glutamine deprivation resulted in a significant increase in the S-phase after 72 h of glutamine deprivation in the MCF-7 cell line. Apoptosis induction resulted in a decrease in viable cells in all cell lines following glutamine deprivation. In the MCF-7 cells, 87.61% of viable cells were present after 24 h of glutamine deprivation.ConclusionThis study demonstrates that glutamine deprivation resulted in decreased cell proliferation, time-dependent- and cell line-dependent ROS generation, aberrant mitochondrial membrane potential and disrupted cell cycle progression. In addition, the estrogen receptor positive MCF-7 cell line was more prominently affected. This study contributes to knowledge regarding the sensitivity of breast cancer cells and non-tumorigenic cells to glutamine deprivation.

Dataset Information

DDIT3 Directs a Dual Mechanism to Balance Glycolysis and Oxidative Phosphorylation during Glutamine Deprivation.

Publications

DDIT3 Directs a Dual Mechanism to Balance Glycolysis and Oxidative Phosphorylation during Glutamine Deprivation.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets