基于细胞器的AMPK的区域化调控与代谢稳态调控

细胞器在细胞代谢中起重要作用，并通过彼此的相互作用介导了众多的代谢过程。然而，它们如何响应胞内胞外的各种应激状态并维持代谢稳态还尚未清楚。我们之前发现了AMPK——一种在维持代谢稳态中至关重要的激酶——在葡萄糖水平下降时的激活是在溶酶体表面进行的，还发现这一过程的溶酶体路径即是葡萄糖感知通路。进一步的研究（前期工作）表明，AMPK的激活事实上发生在内质网-溶酶体接触区域内，且需要内质网上的阳离子通道的参与，以及激活的AMPK能够抑制内质网上相关的胆固醇合成，这表明溶酶体与内质网通过相互作用维持代谢平衡。我们还发现，不同物质或能量的应激状态能够引起不同细胞器定位的AMPK的激活，相应地调节定位在不同细胞器上的底物。本项目拟深入阐明内质网、溶酶体、线粒体等细胞器及其互作在感受葡萄糖水平及其他应激中维持代谢稳态的分子机制和生理意义，为预防和治疗代谢性疾病提供重要的线索和依据。

The cellular organelles play vital roles in cellular metabolic regulation, mediating a wide variety of metabolic processes. It has been increasingly appreciated that organelles intimately crosstalk with each other. However, the molecular mechanisms underlying their responses to intracellular or extracellular metabolic stresses remain obscure. AMPK is a master regulator of metabolic homeostasis; it is activated after phosphorylated by LKB1, in addition to others, when cellular energy is decreased or in response to deprivation of nutrients such as glucose. We have found that AXIN is the scaffold for bridging LKB1 to AMPK inside the cell (Cell Metabolism, 2013), and that AMPK is activated on the surface of lysosomes in response to decreased glucose levels through the lysosomal pathway (Cell Metabolism, 2014, 2016). We have also found that the lysosomal AMPK pathway is to sense glucose in addition to its canonical role in energy sensing (Nature, 2017). Our further studies, i.e. preliminary results for this proposal, showed that a family of cation channels located on the ER surface regulates lysosomal AMPK activation at ER-lysosome contact sites, and that the lysosomally activated AMPK is able to phosphorylate ER-localized SREBP1, a critical regulator of cholesterol synthesis, suggesting that there is a major cross-talk between the lysosome and ER in mediating AMPK activation in response to lowered glucose. In addition, we have obtained new data that indicate different pools of AMPK modulate differently compartmentalized substrates in response to different severities of nutrient/energy stresses or mitochondria-damaging drugs. Detailed characterization of which would provide a comprehensive understanding of distinct roles of AMPK in maintaining metabolic homeostasis under different challenges. In this proposal, we aim to further explore the molecular mechanisms for AMPK activation in the glucose sensing process, and elucidate how the compartmentalized AMPK pools regulate distinct substrates distributed among different organelles such as ER, lysosomes and mitochondria. This study will also help identify novel target for the prevention and treatment of metabolic diseases.