Volume 29, No 6, Jun 2019

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

Volume 29 Issue 6, June 2019: 460-473

ORIGINAL ARTICLES

Hierarchical activation of compartmentalized pools of AMPK depends on severity of nutrient or energy stress

Yue Zong¹ , Chen-Song Zhang¹ , Mengqi Li¹ , Wen Wang ^2,3 , Zhichao Wang ^2,3 , Simon A. Hawley ⁴ , Teng Ma ¹ , Jin-Wei Feng ¹ , Xiao Tian ¹,Qu Qi¹ , Yu-Qing Wu¹ , Cixiong Zhang¹ , Zhiyun Ye¹ , Shu-Yong Lin ¹, Hai-Long Piao ^2,3 , D. Grahame Hardie ⁴ and Sheng-Cai Lin ¹

¹ State Key Laboratory for Cellular Stress Biology, School of Life Sciences, Xiamen University, 361102 Fujian, China; ²CAS Key Laboratory of Separation Science for Analytical Chemistry, Dalian Institute of Chemical Physics, Chinese Academy of Sciences, 116023 Dalian, China; ³University of Chinese Academy of Sciences, 100049 Beijing, China and ⁴Division of Cell Signalling and Immunology, College of Life Sciences, University of Dundee, DD1 5EH Dundee, Scotland, UK
Correspondence: Sheng-Cai Lin (linsc@xmu.edu.cn) These authors contributed equally: Yue Zong, Chen-Song Zhang, Mengqi Li, Wen Wang

AMPK, a master regulator of metabolic homeostasis, is activated by both AMP-dependent and AMP-independent mechanisms. The conditions under which these different mechanisms operate, and their biological implications are unclear. Here, we show that, depending on the degree of elevation of cellular AMP, distinct compartmentalized pools of AMPK are activated, phosphorylating different sets of targets. Low glucose activates AMPK exclusively through the AMP-independent, AXIN-based pathway in lysosomes to phosphorylate targets such as ACC1 and SREBP1c, exerting early anti-anabolic and pro-catabolic roles. Moderate increases in AMP expand this to activate cytosolic AMPK also in an AXIN-dependent manner. In contrast, high concentrations of AMP, arising from severe nutrient stress, activate all pools of AMPK independently of AXIN. Surprisingly, mitochondrion-localized AMPK is activated to phosphorylate ACC2 and mitochondrial fission factor (MFF) only during severe nutrient stress. Our findings reveal a spatiotemporal basis for hierarchical activation of different pools of AMPK during differing degrees of stress severity.

https://doi.org/10.1038/s41422-019-0163-6

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