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

Research output: Contribution to journalArticle

9 Scopus citations

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. 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.

Original languageEnglish (US)
Pages (from-to)508-524.e12
JournalCell Metabolism
Volume30
Issue number3
DOIs
StatePublished - Sep 3 2019

Keywords

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

ASJC Scopus subject areas

  • Physiology
  • Molecular Biology
  • Cell Biology

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  • 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