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

Yue Zong, Chen-Song Zhang, Mengqi Li, Wen Wang, Zhichao Wang, Simon A. Hawley, Teng Ma, Jin-Wei Feng, Xiao Tian, Qu Qi, Yu-Qing Wu, Cixiong Zhang, Zhiyun Ye, Shu-Yong Lin, Hai-Long Piao, D. Grahame Hardie, Sheng-Cai Lin (Lead / Corresponding author)

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Abstract

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.

Original languageEnglish
Pages (from-to)460-473
Number of pages14
JournalCell Research
Volume29
Early online date4 Apr 2019
DOIs
Publication statusE-pub ahead of print - 4 Apr 2019

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  • Cite this

    Zong, Y., Zhang, C-S., Li, M., Wang, W., Wang, Z., Hawley, S. A., Ma, T., Feng, J-W., Tian, X., Qi, Q., Wu, Y-Q., Zhang, C., Ye, Z., Lin, S-Y., Piao, H-L., Hardie, D. G., & Lin, S-C. (2019). Hierarchical activation of compartmentalized pools of AMPK depends on severity of nutrient or energy stress. Cell Research, 29, 460-473. https://doi.org/10.1038/s41422-019-0163-6