1. Academic Validation
  2. 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.
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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