Glutaminase GLS1 senses glutamine availability in a non-enzymatic manner triggering mitochondrial fusion
- 生命科学－已发表论文 
【Abstract】The biological importance of glutamine lies in its being a major source of carbon and nitrogen for both catabolic and anabolic demands. Glutamine is converted to glutamate and then to α-ketoglutarate (α-KG), a catabolic process known as glutaminolysis. α-KG enters the tricarboxylic acid (TCA) cycle, referred to as anaplerosis, not only for the generation of ATP via oxidative phosphorylation, but also for the production of acetyl-coA as a critical precursor for the synthesis of lipids and nucleotides. This is particularly true in cancer cells where glutamine is even considered as a conditionally essential amino acid because its cellular demand often exceeds the rate of self-supply, owing to glucose being ineffectively utilized for energy production through aerobic glycolysis and diversion to biosynthesis.Glutamine also plays a vital role in clearing reactive oxygen species (ROS), not only by providing the precursors glutamate and cysteine for the synthesis of GSH, but also by promoting the production of NADPH via glutamate dehydrogenase (GLUD) or the aspartate/malate shuttle.In cancer cells, deprivation of glutamine results in a large increase of ROS, damaging the structure and function of mitochondria.When the glutamine level is low, mitochondria undergo fusion to maximize efficiency by diluting damaged mitochondrial proteins such as components of the respiratory chain complexes, and repair damage to preserve the integrity of mitochondrial DNA.Three dynamin-like GTPases, mitofusin 1 (MFN1) and mitofusin 2 (MFN2) on the mitochondrial outer membrane, and optic atrophy 1 (OPA1) anchored to the mitochondrial inner membrane, are known to be involved in mitochondrial fusion.However, little is known about how the signal of glutamine shortage is sensed and transmitted to maintain the quality of mitochondria.
Description我校生命科学学院林圣彩教授课题组发现了细胞感应谷氨酰胺并调节线粒体形态的感受器，更新了人们对于线粒体形态的动态调节和代谢稳态调节方式的认识。在这项研究中，研究人员首先证实了是谷氨酰胺本身而不是其上下游的某个代谢产物的缺失引起了线粒体的融合。林圣彩教授课题组还在新发现的GLS1作为谷氨酰胺感受器这一分子模型下观察了谷氨酰胺缺乏的情况下线粒体融合消除ROS的现象，证明了敲低GLS1，或者导入不能引起线粒体融合的GLS1突变体，谷氨酰胺缺乏能引起严重的细胞内ROS水平升高。该研究不但阐述了谷氨酰胺酶GLS1作为谷氨酰胺感受器的分子机制，还揭示了谷氨酰胺酶GLS1作为代谢酶之外的又一重要生物学功能，即非酶功能，与他们实验室之前发现葡萄糖酵解通路中的醛缩酶（aldolase）是感知葡萄糖水平的感受器分子，如出一辙。该论文的通讯作者为我校生命科学学院林圣彩教授及其课题组的博后张宸崧博士。This work was supported by grants from the 973 Program of China (2014CB910602) and the National Natural Science Foundation of China (#31690101, #31430094, and #31600633).
CitationCell Research,2018:https://doi.org/10.1038/s41422-018- 0057-z