Hierarchical activation of compartmentalized pools of AMPK depends on severity of nutrient or energy stress
Hierarchical activation of compartmentalized pools of AMPK depends on severity of nutrient or energy stress
复制标题
AMPK 区室池的分层激活取决于营养或能量应激的严重程度
DOI：
10.1038/s41422-019-0163-6
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发表时间：
2019
期刊：
影响因子：
44.1
通讯作者：
Lin Sheng Cai
中科院分区：
文献类型：
--
作者：
Zong Yue;Zhang Chen Song;Li Mengqi;Wang Wen;Wang Zhichao;Hawley Simon A;Ma Teng;Feng Jin Wei;Tian Xiao;Qi Qu;Wu Yu Qing;Zhang Cixiong;Ye Zhiyun;Lin Shu Yong;Piao Hai Long;Hardie D Grahame;Lin Sheng Cai
AMPK是代谢稳态的主要调节因子，通过AMP依赖性和AMP非依赖性机制激活。这些不同机制运作的条件及其生物学意义尚不清楚。在这里，我们表明，根据细胞AMP的升高程度，不同的AMPK区室池被激活，磷酸化不同的目标集。低葡萄糖仅通过溶酶体中AMP非依赖性、基于AXIN的途径激活AMPK，使ACC1和SREBP1c等靶点磷酸化，发挥早期抗合成代谢和促分解代谢作用。AMP的适度增加也以轴蛋白依赖性方式扩大这种激活胞质AMPK。相反，高浓度的AMP，由严重的营养胁迫引起，激活所有池的AMPK独立轴。令人惊讶的是，仅在严重的营养胁迫期间，位于线粒体的AMPK被激活以磷酸化ACC 2和线粒体裂变因子（MFF）。我们的研究结果揭示了时空的基础上分层激活不同池的AMPK在不同程度的压力严重程度。
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.