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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...
Autores principales: | , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Nature Publishing Group UK
2022
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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 |
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author | 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 |
author_facet | 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 |
author_sort | Ma, Teng |
collection | PubMed |
description | 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. |
format | Online Article Text |
id | pubmed-8891018 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | Nature Publishing Group UK |
record_format | MEDLINE/PubMed |
spelling | pubmed-88910182022-03-22 Low-dose metformin targets the lysosomal AMPK pathway through PEN2 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 Nature Article 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. Nature Publishing Group UK 2022-02-23 2022 /pmc/articles/PMC8891018/ /pubmed/35197629 http://dx.doi.org/10.1038/s41586-022-04431-8 Text en © The Author(s) 2022 https://creativecommons.org/licenses/by/4.0/Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) . |
spellingShingle | Article 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 Low-dose metformin targets the lysosomal AMPK pathway through PEN2 |
title | Low-dose metformin targets the lysosomal AMPK pathway through PEN2 |
title_full | Low-dose metformin targets the lysosomal AMPK pathway through PEN2 |
title_fullStr | Low-dose metformin targets the lysosomal AMPK pathway through PEN2 |
title_full_unstemmed | Low-dose metformin targets the lysosomal AMPK pathway through PEN2 |
title_short | Low-dose metformin targets the lysosomal AMPK pathway through PEN2 |
title_sort | low-dose metformin targets the lysosomal ampk pathway through pen2 |
topic | Article |
url | 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 |
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