The Mechanism Of DDIT3 In Regulating Glycolysis And Mitochondrial Respiration During Glutamine Starvation

Metabolism disorder is one of the hallmarks of cancer,which plays an important role in tumor development.In the late 1920s,scientists discovered that tumor preferred to utilize aerobic glycolysis to provide energy and resulted in an acidic,hypoxic microenvironment,which is called "Warburg effect".The reason why cancer cells prefer aerobic glycolysis may be that glycolysis can generate ATP faster with sufficient glucose;and the metabolic intermediates of glycolysis can be involved with synthesis of nucleotides and amino acids;besides,there is no harmful oxides production during glycolysis,such as ROS;in addition,because of the rapid proliferation but lack of vascular support,cancer cells are often faced with hypoxia in the microenvironment which glycolysis can be perfectly adapted to this condition.It is worthy of note that metabolic reprogramming is vital to ensure the survival of cancer cells during its response to the stress of nutrient starvation.Here,we give more attention to the metabolic reprogramming under glutamine starvation.As one of the important non-essential amino acids,glutamine is known to exert pleiotropic effects on cell metabolism,signaling and stress responses.For instance,the metabolic intermediates of glutamine can provide as carbon source for synthesis of proteins or lipids,and nitrogen source for synthesis of ribonucleotides or other amino acids,what’s more,glutamine metabolism can produce important reductive glutathione(GSH)and NADPH,which play an important role in maintaining redox homeostasis in cancer cells.Therefore,glutamine starvation can induce a series of stress reactions in tumor cells,such as cell cycle arrest,autophagy,apoptosis,etc.However,the molecular mechanisms underlying metabolic reprogramming adapting to glutamine starvation are few reported.Herein we establish that glutaminedeprivation increases DDIT3 expression through GCN2-ATF4 axis mediated transcription,with DDIT3 localized to both the cell nucleus and mitochondria,which ensure DDIT3 to fulfil discrete roles in the compartmentalized pools.First,acting in its capacity as a transcription factor,DDIT3 promotes glycolysis though suppressing TIGAR,a negative regulator of glycolysis.Secondly,mitochondrial localization of DDIT3 attenuates mitochondrial respiration by down-regulation of COQ9 and COX4 through protease LONP1 which impairs electron transport chain(ETC)function.Furthermore,creating a DDIT3 knockout strain of mice established these mechanisms were only induced in wildtype but not knockout mice fed a diet lacking glutamine.Thus,in cells deprived of glutamine,vital ATP levels are maintained through glycolysis while mitochondrial respiration is dampened to avoid deleterious production of ROS.The discrete but coordinated actions of DDIT3 therefore contribute to metabolic reprogramming,serving to balance glycolysis against oxidative phosphorylation and allowing cancer cells to survive metabolic stress conditions.