Details

Autor(en) / Beteiligte

• Ma, Teng
• Tian, Xiao
• Zhang, Baoding
• Li, Mengqi
• Wang, Yu
• Yang, Chunyan
• Wu, Jianfeng
• Wei, Xiaoyan
• Qu, Qi
• Yu, Yaxin
• Long, Shating
• Feng, Jin-Wei
• Li, Chun
• Zhang, Cixiong
• Xie, Changchuan
• Wu, Yaying
• Xu, Zheni
• Chen, Junjie
• Yu, Yong
• Huang, Xi
• He, Ying
• Yao, Luming
• Zhang, Lei
• Zhu, Mingxia
• Wang, Wen
• Wang, Zhi-Chao
• Zhang, Mingliang
• Bao, Yuqian
• Jia, Weiping
• Lin, Shu-Yong
• Ye, Zhiyun
• Piao, Hai-Long
• Deng, Xianming
• Zhang, Chen-Song
• Lin, Sheng-Cai

Titel

Low-dose metformin targets the lysosomal AMPK pathway through PEN2

Ist Teil von

• Nature (London), 2022-03, Vol.603 (7899), p.159-165

Ort / Verlag

England: Nature Publishing Group

Erscheinungsjahr

2022

Quelle

MEDLINE

Beschreibungen/Notizen

• Metformin, the most prescribed antidiabetic medicine, has shown other benefits such as anti-ageing and anticancer effects . For clinical doses of metformin, AMP-activated protein kinase (AMPK) has a major role in its mechanism of action ; 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 . We synthesize a photoactive metformin probe and identify PEN2, a subunit of γ-secretase , 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 , 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.