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  3. Low-dose metformin targets the lysosomal AMPK pathway through PEN2

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

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. xmdeng@xmu.edu.cn.
  • 7 State Key Laboratory for Cellular Stress Biology, Innovation Centre for Cell Signalling Network, School of Life Sciences, Xiamen University, Fujian, China. cszhang@xmu.edu.cn.
  • 8 State Key Laboratory for Cellular Stress Biology, Innovation Centre for Cell Signalling Network, School of Life Sciences, Xiamen University, Fujian, China. linsc@xmu.edu.cn.
  • # 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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