AMPK targets PDZD8 to trigger carbon source shift from glucose to glutamine  

作　　者：Mengqi Li Yu Wang Xiaoyan Wei Wei-Feng Cai Jianfeng Wu Mingxia Zhu Yongliang Wang Yan-Hui Liu Jinye Xiong Qi Qu Yan Chen Xiao Tian Luming Yao Renxiang Xie Xiaomin Li Siwei Chen Xi Huang Cixiong Zhang Changchuan Xie Yaying Wu Zheni Xu Baoding Zhang Bin Jiang Zhi-Chao Wang Qinxi Li Gang Li Shu-Yong Lin Li Yu Hai-Long Piao Xianming Deng Jiahuai Han Chen-song Zhang Sheng-Cai Lin 

机构地区：[1]state Key Laboratory for Cellular Stress Biology,School of Life Sciences,Xiamen University,Xiamen,Fujian,China [2]Xiamen Key Laboratory of Radiation Oncology,Xiamen Cancer Center,The First Affliated Hospital of Xiamen University,School of Medicine,Xiamen University,Xiamen,Fujian,China [3]Laboratory Animal Research Centre,Xiamen University,Xiamen,Fujian,China [4]School of Basic Medical Sciences,Henan University,Kaifeng,Henan,China [5]State Key Laboratory of Membrane Biology,Tsinghua University-Peking University Joint Center for Life Sciences,School of Life Sciences,Tsinghua University,Beijing,China [6]School of Pharmacy,Zhejiang Chinese Medical University,Hangzhou,Zhejiang,China [7]Xiamen Cardiovascular Hospital of Xiamen University,School of Medicine,Xiamen University,Xiamen,Fujian,China [8]CAS Key Laboratory of Separation Science for Analytical Chemistry,Dalian Institute of Chemical Physics,Chinese Academy of Sciences,Dalian,Liaoning,China.

出　　处：《Cell Research》2024年第10期683-706,共24页细胞研究（英文版）

基　　金：supported by grants from the National Key R&D Program of China(2020YFA0803402);the National Natural Science Foundation of China(#92057204,#82088102,#32070753,#31900542,#91854208,#31922034,and#323B2035);the Fundamental Research Funds for the Central Universities(#20720200069);the Project"111"sponsored by the State Bureau of Foreign Experts and Ministry of Education of China(#BP2018017);the Joint Funds for the Innovation of Science and Technology,Fujan province(2021Y9232,2021Y9227,2023Y9448);the Fujian provincial health technology project(2022ZD01005,2022ZQNZD009);the Special Research Funds for Local Science and Technology Development Guided by Central Government(2023L3020);the XMU Fujian Cancer Hospital cooperation grant for the Research Center of Metabolism and Tumor,the XMU Training Program of Innovation and Entrepreneurship for Undergraduates(2021x1183 and 2022Y1233);the Agilent Applications and Core Technology-University Research Grant(#4769).

摘　　要：The shift of carbon utilization from primarily glucose to other nutrients is a fundamental metabolic adaptation to cope with decreased blood glucose levels and the consequent decline in glucose oxidation.AMP-activated protein kinase(AMPK)plays crucial roles in this metabolic adaptation.However,the underlying mechanism is not fully understood.Here,we show that PDZ domain containing 8(PDZD8),which we identify as a new substrate of AMPK activated in low glucose,is required for the low glucosepromoted glutaminolysis.AMPK phosphorylates PDZD8 at threonine 527(T527)and promotes the interaction of PDZD8 with and activation of glutaminase 1(GLS1),a rate-limiting enzyme of glutaminolysis.In vivo,the AMPK-PDZD8-GLS1 axis is required for the enhancement of glutaminolysis as tested in the skeletal muscle tissues,which occurs earlier than the increase in fatty acid utilization during fasting.The enhanced glutaminolysis is also observed in macrophages in low glucose or under acute lipopolysaccharide(LPS)treatment.Consistent with a requirement of heightened glutaminolysis,the PDZD8-T527A mutation dampens the secretion of pro-inflammatory cytokines in macrophages in mice treated with LPs.Together,we have revealed an AMPK-PDZD8-GLS1 axis that promotes glutaminolysis ahead of increased fatty acid utilization under glucose shortage.

关 键 词：AMPK PDZ TOGETHER 

分 类 号：R58[医药卫生—内分泌]