TY - JOUR
T1 - Hierarchical activation of compartmentalized pools of AMPK depends on severity of nutrient or energy stress
AU - Zong, Yue
AU - Zhang, Chen-Song
AU - Li, Mengqi
AU - Wang, Wen
AU - Wang, Zhichao
AU - Hawley, Simon A.
AU - Ma, Teng
AU - Feng, Jin-Wei
AU - Tian, Xiao
AU - Qi, Qu
AU - Wu, Yu-Qing
AU - Zhang, Cixiong
AU - Ye, Zhiyun
AU - Lin, Shu-Yong
AU - Piao, Hai-Long
AU - Hardie, D. Grahame
AU - Lin, Sheng-Cai
N1 - ACC1-floxed mouse (Stock No. 030954, The Jackson Laboratory) was a generous gift from Prof. Jay Horton (UT Southwestern Medical Center), and the ACC2−/− mouse from Prof. Tian Xu (Institute of Developmental Biology and Molecular Medicine, Fudan University). Heterotrimeric AMPK cloned into pET21b was a generous gift from Prof. Dietbert Neumann (Swiss Federal Institute of Technology). We also thank Jiayuan Zhang from Xiamen University for the artwork of Fig. 4a. This work was supported by grants from the National Key R&D Program of China (2016YFA0502001) and the National Natural Science Foundation of China (#31730058, #31430094, #31601152 and #31690101) through S-C.L., by the Open Research Fund of State Key Laboratory of Cellular Stress Biology, Xiamen University (SKLCSB2017KF002) through H-L.P., and by Wellcome Trust (204766/Z/16/Z) through D.G.H.
PY - 2019/6/1
Y1 - 2019/6/1
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85064004582&partnerID=8YFLogxK
U2 - 10.1038/s41422-019-0163-6
DO - 10.1038/s41422-019-0163-6
M3 - Article
C2 - 30948787
SN - 1001-0602
VL - 29
SP - 460
EP - 473
JO - Cell Research
JF - Cell Research
IS - 6
ER -