Low-dose metformin targets the lysosomal AMPK pathway through PEN2

Teng Ma, Xiao Tian, Baoding Zhang, Mengqi Li, Yu Wang, Chunyan Yang, Jianfeng Wu, Xiaoyan Wei, Qi Qu, Yaxin Yu, Shating Long, Jin-Wei Feng, Chun Li, Cixiong Zhang, Changchuan Xie, Yaying Wu, Zheni Xu, Junjie Chen, Yong Yu, Xi Huang, Ying He, Luming Yao, Lei Zhang, Mingxia Zhu, Wen Wang, Zhi-Chao Wang, Mingliang Zhang, Yuqian Bao, Weiping Jia, Shu-Yong Lin, Zhiyun Ye, Hai-Long Piao, Xianming Deng (), Chen-Song Zhang () and Sheng-Cai Lin ()
Additional contact information
Teng Ma: Xiamen University
Xiao Tian: Xiamen University
Baoding Zhang: Xiamen University
Mengqi Li: Xiamen University
Yu Wang: Xiamen University
Chunyan Yang: Xiamen University
Jianfeng Wu: Xiamen University
Xiaoyan Wei: Xiamen University
Qi Qu: Xiamen University
Yaxin Yu: Xiamen University
Shating Long: Xiamen University
Jin-Wei Feng: Xiamen University
Chun Li: Xiamen University
Cixiong Zhang: Xiamen University
Changchuan Xie: Xiamen University
Yaying Wu: Xiamen University
Zheni Xu: Xiamen University
Junjie Chen: Xiamen University
Yong Yu: Xiamen University
Xi Huang: Xiamen University
Ying He: Xiamen University
Luming Yao: Xiamen University
Lei Zhang: Xiamen University
Mingxia Zhu: Xiamen University
Wen Wang: Dalian Institute of Chemical Physics, Chinese Academy of Sciences
Zhi-Chao Wang: Dalian Institute of Chemical Physics, Chinese Academy of Sciences
Mingliang Zhang: Shanghai Diabetes Institute, Shanghai Key Laboratory of Diabetes Mellitus, Shanghai Jiao Tong University Affiliated Sixth People’s Hospital
Yuqian Bao: Shanghai Diabetes Institute, Shanghai Key Laboratory of Diabetes Mellitus, Shanghai Jiao Tong University Affiliated Sixth People’s Hospital
Weiping Jia: Shanghai Diabetes Institute, Shanghai Key Laboratory of Diabetes Mellitus, Shanghai Jiao Tong University Affiliated Sixth People’s Hospital
Shu-Yong Lin: Xiamen University
Zhiyun Ye: Xiamen University
Hai-Long Piao: Dalian Institute of Chemical Physics, Chinese Academy of Sciences
Xianming Deng: Xiamen University
Chen-Song Zhang: Xiamen University
Sheng-Cai Lin: Xiamen University

Nature, 2022, vol. 603, issue 7899, 159-165

Abstract: Abstract Metformin, the most prescribed antidiabetic medicine, has shown other benefits such as anti-ageing and anticancer effects1–4. For clinical doses of metformin, AMP-activated protein kinase (AMPK) has a major role in its mechanism of action4,5; 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 starvation6. We synthesize a photoactive metformin probe and identify PEN2, a subunit of γ-secretase7, 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-ATPase8, 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.

Date: 2022
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DOI: 10.1038/s41586-022-04431-8

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