Li 2024 Cell Res
| Li M, Wang Y, Wei X, Cai WF, Wu J, Zhu M, Wang Y, Liu YH, Xiong J, Qu Q, Chen Y, Tian X, Yao L, Xie R, Li X, Chen S, Huang X, Zhang C, Xie C, Wu Y, Xu Z, Zhang B, Jiang B, Wang ZC, Li Q, Li G, Lin SY, Yu L, Piao HL, Deng X, Han J, Zhang CS, Lin SC (2024) AMPK targets PDZD8 to trigger carbon source shift from glucose to glutamine. Cell Res [Epub ahead of print]. https://doi.org/10.1038/s41422-024-00985-6 |
Li Mengqi, Wang Yu, Wei Xiaoyan, Cai Wei-Feng, Wu Jianfeng, Zhu Mingxia, Wang Yongliang, Liu Yan-Hui, Xiong Jinye, Qu Qi, Chen Yan, Tian Xiao, Yao Luming, Xie Renxiang, Li Xiaomin, Chen Siwei, Huang Xi, Zhang Cixiong, Xie Changchuan, Wu Yaying, Xu Zheni, Zhang Baoding, Jiang Bin, Wang Zhi-Chao, Li Qinxi, Li Gang, Lin Shu-Yong, Yu Li, Piao Hai-Long, Deng Xianming, Han Jiahuai, Zhang Chen-Song, Lin Sheng-Cai (2024) Cell Res
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.
• Bioblast editor: Plangger M • O2k-Network Lab: CN Xiamen Lin SC
Labels: MiParea: Respiration, Genetic knockout;overexpression
Organism: Mouse
Tissue;cell: Skeletal muscle
Preparation: Permeabilized tissue
Coupling state: ET, LEAK, OXPHOS
Pathway: N, NS
HRR: Oxygraph-2k
2024-06, CN
