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

Mengqi Li, Chen-Song Zhang, Yue Zong, Jin-Wei Feng, Teng Ma, Meiqin Hu, Zhizhong Lin, Xiaotong Li, Changchuan Xie, Yaying Wu, Dong Jiang, Ying Li, Cixiong Zhang, Xiao Tian, Wen Wang, Yanyan Yang, Jie Chen, Jiwen Cui, Yu-Qing Wu, Xin ChenQing-Feng Liu, Jianfeng Wu, Shu-Yong Lin, Zhiyun Ye, Ying Liu, Hai-Long Piao, Li Yu, Zhuan Zhou, Xiao-Song Xie, D. Grahame Hardie, Sheng-Cai Lin

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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' 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.

Original languageEnglish
Pages (from-to)508-524.e12
Number of pages17
JournalCell Metabolism
Volume30
Issue number3
Early online date13 Jun 2019
DOIs
Publication statusPublished - 3 Sep 2019

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Keywords

  • AMP-activated protein kinase
  • AMPK
  • TRPV
  • aldolase
  • glucose sensing
  • transient receptor potential channels
  • v-ATPase

Cite this

Li, M., Zhang, C-S., Zong, Y., Feng, J-W., Ma, T., Hu, M., Lin, Z., Li, X., Xie, C., Wu, Y., Jiang, D., Li, Y., Zhang, C., Tian, X., Wang, W., Yang, Y., Chen, J., Cui, J., Wu, Y-Q., ... Lin, S-C. (2019). Transient Receptor Potential V Channels Are Essential for Glucose Sensing by Aldolase and AMPK. Cell Metabolism, 30(3), 508-524.e12. https://doi.org/10.1016/j.cmet.2019.05.018