Volume 34, No 10, Oct 2024

ISSN: 1001-0602 
EISSN: 1748-7838 2018 
impact factor 17.848* 
(Clarivate Analytics, 2019)

Volume 34 Issue 10, October 2024: 683-706   |  Open Access

ORIGINAL ARTICLES

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

Mengqi Li^1,† , Yu Wang^1,† , Xiaoyan Wei^1,† , Wei-Feng Cai^2,† , Jianfeng Wu^3,† , Mingxia Zhu¹ , Yongliang Wang⁴ , Yan-Hui Liu¹ , Jinye Xiong¹ , Qi Qu¹ , Yan Chen¹ , Xiao Tian¹ , Luming Yao¹ , Renxiang Xie⁵ , Xiaomin Li⁵ , Siwei Chen¹ , Xi Huang¹ , Cixiong Zhang¹ , Changchuan Xie¹ , Yaying Wu¹ , Zheni Xu¹ , Baoding Zhang¹ , Bin Jiang¹ , Zhi-Chao Wang⁶ , Qinxi Li¹ , Gang Li⁷ , Shu-Yong Lin¹ , Li Yu⁵ , Hai-Long Piao⁸ , Xianming Deng¹ , Jiahuai Han¹ , Chen-Song Zhang^1,* , Sheng-Cai Lin^1,*

¹State Key Laboratory for Cellular Stress Biology, School of Life Sciences, Xiamen University, Xiamen, Fujian, China
²Xiamen Key Laboratory of Radiation Oncology, Xiamen Cancer Center, The First Affiliated Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen, Fujian, China
³Laboratory Animal Research Centre, Xiamen University, Xiamen, Fujian, China
⁴School of Basic Medical Sciences, Henan University, Kaifeng, Henan, China
⁵State Key Laboratory of Membrane Biology, Tsinghua University-Peking University Joint Center for Life Sciences, School of Life Sciences, Tsinghua University, Beijing, China
⁶School of Pharmacy, Zhejiang Chinese Medical University, Hangzhou, Zhejiang, China
⁷Xiamen Cardiovascular Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen, Fujian, China
⁸CAS Key Laboratory of Separation Science for Analytical Chemistry, Dalian Institute of Chemical Physics, Chinese Academy of Sciences, Dalian, Liaoning, China
^†These authors contributed equally: Mengqi Li, Yu Wang, Xiaoyan Wei, Wei-Feng Cai, Jianfeng Wu
Correspondence: Chen-Song Zhang(cszhang@xmu.edu.cn)Sheng-Cai Lin(linsc@xmu.edu.cn)

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.

https://doi.org/10.1038/s41422-024-00985-6

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