2. Academic Validation
  3. AMPK targets PDZD8 to trigger carbon source shift from glucose to glutamine

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

  • Cell Res. 2024 Jun 19. doi: 10.1038/s41422-024-00985-6.
Mengqi Li # 1,  Yu Wang # 1,  Xiaoyan Wei # 1,  Wei-Feng Cai # 2,  Jianfeng Wu # 3,  Mingxia Zhu 1,  Yongliang Wang 4,  Yan-Hui Liu 1,  Jinye Xiong 1,  Qi Qu 1,  Yan Chen 1,  Xiao Tian 1,  Luming Yao 1,  Renxiang Xie 5,  Xiaomin Li 5,  Siwei Chen 1,  Xi Huang 1,  Cixiong Zhang 1,  Changchuan Xie 1,  Yaying Wu 1,  Zheni Xu 1,  Baoding Zhang 1,  Bin Jiang 1,  Zhi-Chao Wang 6,  Qinxi Li 1,  Gang Li 7,  Shu-Yong Lin 1,  Li Yu 5,  Hai-Long Piao 8,  Xianming Deng 1,  Jiahuai Han 1,  Chen-Song Zhang 9,  Sheng-Cai Lin 10
Affiliations

Affiliations

  • 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 Affiliated 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.
  • 9 State Key Laboratory for Cellular Stress Biology, School of Life Sciences, Xiamen University, Xiamen, Fujian, China. cszhang@xmu.edu.cn.
  • 10 State Key Laboratory for Cellular Stress Biology, School of Life Sciences, Xiamen University, Xiamen, Fujian, China. linsc@xmu.edu.cn.
  • # Contributed equally.
PMID: 38898113 DOI: 10.1038/s41422-024-00985-6
Abstract

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 glucose-promoted 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.

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