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...

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Published in:	Nature (London) Vol. 603; no. 7899; pp. 159 - 165
Main Authors:	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
Format:	Journal Article
Language:	English
Published:	London Nature Publishing Group UK 03.03.2022 Nature Publishing Group
Subjects:	13/1 13/109 13/44 13/51 13/95 14/19 14/28 140/131 38/77 631/443/319 631/80/86 64/11 64/60 82/103 82/80 Adenosine Triphosphatases - metabolism Aging AMP-activated protein kinase AMP-Activated Protein Kinases - metabolism Amyloid Precursor Protein Secretases Animals Antidiabetics Binding sites Caenorhabditis elegans - metabolism Chemoreception Diabetes Diabetes mellitus Diabetes Mellitus - drug therapy Dissociation Glucose Glucose - metabolism H+-transporting ATPase Humanities and Social Sciences Humans Hypoglycemic Agents - administration & dosage Hypoglycemic Agents - metabolism Hypoglycemic Agents - pharmacology Intestine Kinases Life span Localization Lysosomes - metabolism Mass spectrometry Membrane Proteins Metformin Metformin - agonists Metformin - metabolism Metformin - pharmacology Microscopy multidisciplinary Presenilin 2 Proteins Protons Science Science (multidisciplinary) Scientific imaging Signal transduction Vacuolar Proton-Translocating ATPases - metabolism
ISSN:	0028-0836, 1476-4687, 1476-4687
Online Access:	Get full text
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Summary:	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. The molecular target of the antidiabetic medicine metformin is identified as PEN2, a subunit of γ-secretases, and the PEN2–ATP6AP1 axis offers potential targets for screening for metformin substitutes.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 14 content type line 23
ISSN:	0028-0836 1476-4687 1476-4687
DOI:	10.1038/s41586-022-04431-8