The Lysosomal v-ATPase-Ragulator Complex Is a Common Activator for AMPK and mTORC1

AMPK和mTORC1是机体和细胞内最重要的调节代谢稳态的分子。人们已经发现，AMPK复合体能够通过与体内AMP结合从而感知体内AMP/ATP的水平，并在该水平较高（即能量水平较低）的情况下引发其复合体活性的增加。该结果直接导致了多条信号通路的抑制或激活，从而引起一系列的生理变化。其结果是增加体内的产能代谢从而达到稳定体内能量水平的作用。与AMPK相反，mTORC1的激活需要在细胞内能量水平较高的情况下才能发生。mTORC1激活进一步激活了一系列下游分子，这些激活的分子造成的结果也恰恰和AMPK所造成的结果相反：增加耗能的合成代谢从而促进细胞增殖。目前的研究还表明，AMPK和mTORC1在肿瘤...AMPK and mTORC1 are the most important regulators that control metabolic homeostasis in cells and organisms. AMPK complex binds AMP thus sensing intracellular AMP/ADP levels and is activated when AMP/ADP levels increased. Activated AMPK activates or inhibits various signaling pathways, promotes ATP production and balances intracellular energy state. In comparison to AMPK, mTORC1 is activated when ...学位：理学博士院系专业：生命科学学院_生物化学与分子生物学学号：2162012015378

Transient Receptor Potential V Channels Are Essential for Glucose Sensing by Aldolase and AMPK

Fructose-1,6-bisphosphate (FBP) aldolase links sensing of declining glucose availability to AMPK activation via the lysosomal pathway. However, how aldolase transmits lack of occupancy by FBP to AMPK activation remains unclear. Here, we show that FBP-unoccupied aldolase interacts with and inhibits endoplasmic reticulum (ER)-localized transient receptor potential channel subfamily V, inhibiting calcium release in low glucose. The decrease of calcium at contact sites between ER and lysosome renders the inhibited TRPV accessible to bind the lysosomal v-ATPase that then recruits AXIN:LKB1 to activate AMPK independently of AMP. Genetic depletion of TRPVs blocks glucose starvation-induced AMPK activation in cells and liver of mice, and in nematodes, indicative of physical requirement of TRPVs. Pharmacological inhibition of TRPVs activates AMPK and elevates NAD(+) levels in aged muscles, rejuvenating the animals' running capacity. Our study elucidates that TRPVs relay the FBP-free status of aldolase to the reconfiguration of v-ATPase, leading to AMPK activation in low glucose

Glucose-starvation induced AMP-independent activation of AMPK

葡萄糖不仅是生物体能量的主要来源和合成生物分子的主要碳源，其浓度也作为一种“状态信号”调控包括AMPK和mTOR在内的信号通路。之前我们发现了AXIN介导LKB1在溶酶体上激活AMPK和同时抑制mTOR的通路，揭示了合成代谢与分解代谢的切换方式。进一步的工作还发现了细胞感受葡萄糖浓度是通过醛缩酶来介导的，即葡萄糖浓度下降导致的醛缩酶底物果糖-1，6-二磷酸水平的下降是AMPK激活的真正原因。我们发现葡萄糖饥饿并不通过提高AMP浓度来激活AMPK，引发了对AMPK调控模式的重大范式改变。Glucose is not only the main source for cellular energy and biosynthesis of biomolecules, but also serves as a “status signal” that can modulate key signaling pathways for control of metabolic homeostasis, including the master kinases AMPK and mTOR. We previously showed that AXIN acts as a scaffold for LKB1 to activate AMPK on the surface of lysosome, which concomitantly inhibits mTOR signaling, u...学位：博士后院系专业：化学化工学院_生物化学与分子生物学学号：201517006

Glutaminase GLS1 senses glutamine availability in a non-enzymatic manner triggering mitochondrial fusion

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。【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.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)