期刊
ADVANCED SCIENCE
卷 8, 期 11, 页码 -出版社
WILEY
DOI: 10.1002/advs.202003732
关键词
COQ9; COX4; DDIT3; CHOP; electron transfer chain; glutamine deprivation; glycolysis
资金
- National Key R&D Program of China [2018YFA0107100]
- National Natural Science Foundation of China [81820108021, 31871437, 81730074, 81970153]
This study reveals that DDIT3, a stress-responsive transcription factor, plays a crucial role in promoting glycolysis and suppressing mitochondrial respiration in response to glutamine deprivation, enabling tumor cells to survive metabolic stress induced by glutamine starvation.
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.
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