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Low-dose metformin targets the lysosomal AMPK pathway through PEN2

Metformin, the most prescribed antidiabetic medicine, has shown other benefits such as anti-ageing and anticancer effects(1–4). For clinical doses of metformin, AMP-activated protein kinase (AMPK) has a major role in its mechanism of action(4,5); however, the direct molecular target of metformin rem...

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Detalles Bibliográficos
Autores principales: 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
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8891018/
https://www.ncbi.nlm.nih.gov/pubmed/35197629
http://dx.doi.org/10.1038/s41586-022-04431-8
Descripción
Sumario:Metformin, the most prescribed antidiabetic medicine, has shown other benefits such as anti-ageing and anticancer effects(1–4). For clinical doses of metformin, AMP-activated protein kinase (AMPK) has a major role in its mechanism of action(4,5); 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 starvation(6). We synthesize a photoactive metformin probe and identify PEN2, a subunit of γ-secretase(7), 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(8), 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.