期刊
NATURE
卷 603, 期 7899, 页码 159-+出版社
NATURE PORTFOLIO
DOI: 10.1038/s41586-022-04431-8
关键词
-
资金
- National Natural Science Foundation of China [82088102, 91854208, 31922034, 32070753, 31730058, 22025702, 91853203]
- Natural Science Foundation of Fujian Province of China [2020J02003]
- Fundamental Research Funds for the Central Universities [20720200069, 20720200014, 20720190101]
- Programme of Introducing Talents of Discipline to Universities [BP2018017]
- XMU Training Programme of Innovation and Entrepreneurship for Undergraduates [202010384190, 2020X901, 2020X895]
The molecular target of the antidiabetic medicine metformin is identified as PEN2, and the PEN2-ATP6AP1 axis activates the AMPK pathway, providing therapeutic effects without substantial adverse effects.
The molecular target of the antidiabetic medicine metformin is identified as PEN2, a subunit of gamma-secretases, and the PEN2-ATP6AP1 axis offers potential targets for screening for metformin substitutes. Metformin, the most prescribed antidiabetic medicine, has shown other benefits such as anti-ageing and anticancer effects(1-4). For clinical doses of metformin, AMP-activated protein kinase (AMPK) has a major role in its mechanism of action(4,5); however, the direct molecular target of metformin remains unknown. Here we show that clinically relevant concentrations of metformin inhibit the lysosomal proton pump v-ATPase, which is a central node for AMPK activation following glucose starvation(6). We synthesize a photoactive metformin probe and identify PEN2, a subunit of gamma-secretase(7), as a binding partner of metformin with a dissociation constant at micromolar levels. Metformin-bound PEN2 forms a complex with ATP6AP1, a subunit of the v-ATPase(8), which leads to the inhibition of v-ATPase and the activation of AMPK without effects on cellular AMP levels. Knockout of PEN2 or re-introduction of a PEN2 mutant that does not bind ATP6AP1 blunts AMPK activation. In vivo, liver-specific knockout of Pen2 abolishes metformin-mediated reduction of hepatic fat content, whereas intestine-specific knockout of Pen2 impairs its glucose-lowering effects. Furthermore, knockdown of pen-2 in Caenorhabditis elegans abrogates metformin-induced extension of lifespan. Together, these findings reveal that metformin binds PEN2 and initiates a signalling route that intersects, through ATP6AP1, the lysosomal glucose-sensing pathway for AMPK activation. This ensures that metformin exerts its therapeutic benefits in patients without substantial adverse effects.
作者
我是这篇论文的作者
点击您的名字以认领此论文并将其添加到您的个人资料中。
推荐
暂无数据