@article{017f5983b1aa4bf291a7103add6bc1ba,
title = "Transient Receptor Potential V Channels Are Essential for Glucose Sensing by Aldolase and AMPK",
abstract = "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{\textquoteright} 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. Falling levels of glucose, and consequentially fructose-1,6-bisphosphate (FBP), are sensed by glycolytic enzyme aldolase. Li et al. demonstrate that FBP-unoccupied aldolase binds to and inhibits ER-localized TRPV channels, with the decreased calcium at the ER-lysosome contact enabling the channel proteins to interact with lysosomal v-ATPase to allow for AMPK activation.",
keywords = "AMP-activated protein kinase, AMPK, TRPV, aldolase, glucose sensing, transient receptor potential channels, v-ATPase",
author = "Mengqi Li and Zhang, {Chen Song} and Yue Zong and Feng, {Jin Wei} and Teng Ma and Meiqin Hu and Zhizhong Lin and Xiaotong Li and Changchuan Xie and Yaying Wu and Dong Jiang and Ying Li and Cixiong Zhang and Xiao Tian and Wen Wang and Yanyan Yang and Jie Chen and Jiwen Cui and Wu, {Yu Qing} and Xin Chen and Liu, {Qing Feng} and Jianfeng Wu and Lin, {Shu Yong} and Zhiyun Ye and Ying Liu and Piao, {Hai Long} and Li Yu and Zhuan Zhou and Xie, {Xiao Song} and Hardie, {D. Grahame} and Lin, {Sheng Cai}",
note = "Funding Information: This project was supported by grants from the National Natural Science Foundation of China (# 31730058 , # 31430094 , # 31601152 , and # 31690101 ) and from the National Key R&D Program of China ( 2016YFA0502001 ) through S.-C.L. and by Wellcome Trust ( 204766/Z/16/Z ) through D.G.H. We acknowledge Professor Dietbert Neumann (Maastricht University) for providing the tricistronic AMPK expression vector, Professor Zhi-Xin Wang (Tsinghua University) for the technical support on kinetic analysis of CaMKK2 activity, Dr. Terytty Yang Li from Johan Auwerx{\textquoteright}s lab ({\'E}cole Polytechnique F{\'e}d{\'e}rale in Lausanne) for the suggestions on NAD + measurement, and Professors Ying Chen and Zhi Qi (Xiamen University) for the critical discussions on measuring the channel activity of TRPV4. We also acknowledge Jiayuan Zhang and Yongkang Lin for artwork and the Caenorhabditis Genetics Center for supplying nematode strains. Funding Information: This project was supported by grants from the National Natural Science Foundation of China (#31730058, #31430094, #31601152, and #31690101) and from the National Key R&D Program of China (2016YFA0502001) through S.-C.L. and by Wellcome Trust (204766/Z/16/Z) through D.G.H. We acknowledge Professor Dietbert Neumann (Maastricht University) for providing the tricistronic AMPK expression vector, Professor Zhi-Xin Wang (Tsinghua University) for the technical support on kinetic analysis of CaMKK2 activity, Dr. Terytty Yang Li from Johan Auwerx's lab (?cole Polytechnique F?d?rale in Lausanne) for the suggestions on NAD+ measurement, and Professors Ying Chen and Zhi Qi (Xiamen University) for the critical discussions on measuring the channel activity of TRPV4. We also acknowledge Jiayuan Zhang and Yongkang Lin for artwork and the Caenorhabditis Genetics Center for supplying nematode strains. M.L. C.-S.Z. Y.Z. and S.-C.L. conceived the study and designed the experiments. M.L. C.-S.Z. and Y.Z. generated the cell strains and performed the immunoprecipitation, in vitro reconstitution, and the associated western blot analyses with assistance from J.-W.F. T.M. Z.L. D.J. Y.L. X.T. J.C. and Y.-Q.W. M.L. performed the confocal, SIM, and STORM imaging acquisition and analysis with assistance from X.C. and Q.-F.L. M.L. C.-S.Z. Y.Z. and W.J. performed the experiments on aged mice. C.X. and Y.W. performed mass spectrometry analysis. M.L. analyzed the activity of TRPV4 and the levels of Ca2+ concentration with the guidance of M.H. and Z.Z. X.L. generated the antibody for immunoprecipitating endogenous aldolase. C.Z. analyzed NAD+ through HPLC-MS. Y.Z. and W.W. performed the CE-MS-based analysis of adenylates under the guidance of H.-L.P. Y.Y. and J.C. performed the nematode experiments under the guidance of Y.L. L.Y. optimized the method for cell permeabilization when stained for TRPV4. H.-L.P. S.-Y.L. Z.Y. X.-S.X. and D.G.H. helped with discussion and interpretation of results. D.G.H. and S.-C.L. wrote the manuscript. The authors declare no competing interests. Publisher Copyright: {\textcopyright} 2019 The Author(s)",
year = "2019",
month = sep,
day = "3",
doi = "10.1016/j.cmet.2019.05.018",
language = "English (US)",
volume = "30",
pages = "508--524.e12",
journal = "Cell Metabolism",
issn = "1550-4131",
publisher = "Cell Press",
number = "3",
}