Low-dose metformin targets the lysosomal AMPK pathway through PEN2

  • Nature. 2022 Mar;603(7899):159-165. doi: 10.1038/s41586-022-04431-8.
Teng Ma   #  1 ,  Xiao Tian   #  1 ,  Baoding Zhang   #  1 ,  Mengqi Li  1 ,  Yu Wang  1 ,  Chunyan Yang  1 ,  Jianfeng Wu  2 ,  Xiaoyan Wei  1 ,  Qi Qu  1 ,  Yaxin Yu  1 ,  Shating Long  1 ,  Jin-Wei Feng  1 ,  Chun Li  1 ,  Cixiong Zhang  1 ,  Changchuan Xie  1 ,  Yaying Wu  1 ,  Zheni Xu  1 ,  Junjie Chen  3 ,  Yong Yu  1 ,  Xi Huang  1 ,  Ying He  1 ,  Luming Yao  1 ,  Lei Zhang  1 ,  Mingxia Zhu  1 ,  Wen Wang  4 ,  Zhi-Chao Wang  4 ,  Mingliang Zhang  5 ,  Yuqian Bao  5 ,  Weiping Jia  5 ,  Shu-Yong Lin  1 ,  Zhiyun Ye  1 ,  Hai-Long Piao  4 ,  Xianming Deng  6 ,  Chen-Song Zhang  7 ,  Sheng-Cai Lin  8
Affiliations
  • 1. State Key Laboratory for Cellular Stress Biology, Innovation Centre for Cell Signalling Network, School of Life Sciences, Xiamen University, Fujian, China.
  • 2. Laboratory Animal Research Centre, Xiamen University, Fujian, China.
  • 3. Analysis and Measurement Centre, School of Pharmaceutical Sciences, Xiamen University, Fujian, China.
  • 4. CAS Key Laboratory of Separation Science for Analytical Chemistry, Dalian Institute of Chemical Physics, Chinese Academy of Sciences, Liaoning, China.
  • 5. Department of Endocrinology and Metabolism, Shanghai Clinical Centre for Diabetes, Shanghai Diabetes Institute, Shanghai Key Laboratory of Diabetes Mellitus, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai, China.
  • 6. State Key Laboratory for Cellular Stress Biology, Innovation Centre for Cell Signalling Network, School of Life Sciences, Xiamen University, Fujian, China. [email protected].
  • 7. State Key Laboratory for Cellular Stress Biology, Innovation Centre for Cell Signalling Network, School of Life Sciences, Xiamen University, Fujian, China. [email protected].
  • 8. State Key Laboratory for Cellular Stress Biology, Innovation Centre for Cell Signalling Network, School of Life Sciences, Xiamen University, Fujian, China. [email protected].
  • # Contributed equally.
PMID: 35197629 DOI: 10.1038/s41586-022-04431-8
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.

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