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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| Vydáno v: | Nature (London) Ročník 603; číslo 7899; s. 159 - 165 |
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| Hlavní autoři: | , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , |
| Médium: | Journal Article |
| Jazyk: | angličtina |
| Vydáno: |
London
Nature Publishing Group UK
03.03.2022
Nature Publishing Group |
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| ISSN: | 0028-0836, 1476-4687, 1476-4687 |
| On-line přístup: | Získat plný text |
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| Abstract | 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. |
|---|---|
| AbstractList | 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 у-secretase7, as a binding partner of metformin with a dissociation constant at micromolar levels. Metformin-bound PEN2 forms a complex with ATP6AP1, a subunit ofthe 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 metformininduced 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. Metformin, the most prescribed antidiabetic medicine, has shown other benefits such as anti-ageing and anticancer effects . For clinical doses of metformin, AMP-activated protein kinase (AMPK) has a major role in its mechanism of action ; 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 . We synthesize a photoactive metformin probe and identify PEN2, a subunit of γ-secretase , 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 , 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. 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. 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. 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.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. 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. 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. |
| Author | Zhu, Mingxia Ma, Teng Wu, Yaying Wei, Xiaoyan Zhang, Baoding Huang, Xi Wang, Wen Chen, Junjie Qu, Qi Feng, Jin-Wei Li, Chun Xie, Changchuan Bao, Yuqian Zhang, Mingliang He, Ying Li, Mengqi Piao, Hai-Long Yu, Yong Tian, Xiao Deng, Xianming Jia, Weiping Xu, Zheni Wang, Yu Yang, Chunyan Zhang, Cixiong Yao, Luming Lin, Shu-Yong Wu, Jianfeng Zhang, Lei Yu, Yaxin Zhang, Chen-Song Ye, Zhiyun Wang, Zhi-Chao Long, Shating Lin, Sheng-Cai |
| Author_xml | – sequence: 1 givenname: Teng surname: Ma fullname: Ma, Teng organization: State Key Laboratory for Cellular Stress Biology, Innovation Centre for Cell Signalling Network, School of Life Sciences, Xiamen University – sequence: 2 givenname: Xiao surname: Tian fullname: Tian, Xiao organization: State Key Laboratory for Cellular Stress Biology, Innovation Centre for Cell Signalling Network, School of Life Sciences, Xiamen University – sequence: 3 givenname: Baoding surname: Zhang fullname: Zhang, Baoding organization: State Key Laboratory for Cellular Stress Biology, Innovation Centre for Cell Signalling Network, School of Life Sciences, Xiamen University – sequence: 4 givenname: Mengqi surname: Li fullname: Li, Mengqi organization: State Key Laboratory for Cellular Stress Biology, Innovation Centre for Cell Signalling Network, School of Life Sciences, Xiamen University – sequence: 5 givenname: Yu surname: Wang fullname: Wang, Yu organization: State Key Laboratory for Cellular Stress Biology, Innovation Centre for Cell Signalling Network, School of Life Sciences, Xiamen University – sequence: 6 givenname: Chunyan surname: Yang fullname: Yang, Chunyan organization: State Key Laboratory for Cellular Stress Biology, Innovation Centre for Cell Signalling Network, School of Life Sciences, Xiamen University – sequence: 7 givenname: Jianfeng surname: Wu fullname: Wu, Jianfeng organization: Laboratory Animal Research Centre, Xiamen University – sequence: 8 givenname: Xiaoyan surname: Wei fullname: Wei, Xiaoyan organization: State Key Laboratory for Cellular Stress Biology, Innovation Centre for Cell Signalling Network, School of Life Sciences, Xiamen University – sequence: 9 givenname: Qi surname: Qu fullname: Qu, Qi organization: State Key Laboratory for Cellular Stress Biology, Innovation Centre for Cell Signalling Network, School of Life Sciences, Xiamen University – sequence: 10 givenname: Yaxin surname: Yu fullname: Yu, Yaxin organization: State Key Laboratory for Cellular Stress Biology, Innovation Centre for Cell Signalling Network, School of Life Sciences, Xiamen University – sequence: 11 givenname: Shating surname: Long fullname: Long, Shating organization: State Key Laboratory for Cellular Stress Biology, Innovation Centre for Cell Signalling Network, School of Life Sciences, Xiamen University – sequence: 12 givenname: Jin-Wei surname: Feng fullname: Feng, Jin-Wei organization: State Key Laboratory for Cellular Stress Biology, Innovation Centre for Cell Signalling Network, School of Life Sciences, Xiamen University – sequence: 13 givenname: Chun surname: Li fullname: Li, Chun organization: State Key Laboratory for Cellular Stress Biology, Innovation Centre for Cell Signalling Network, School of Life Sciences, Xiamen University – sequence: 14 givenname: Cixiong surname: Zhang fullname: Zhang, Cixiong organization: State Key Laboratory for Cellular Stress Biology, Innovation Centre for Cell Signalling Network, School of Life Sciences, Xiamen University – sequence: 15 givenname: Changchuan orcidid: 0000-0002-1078-0464 surname: Xie fullname: Xie, Changchuan organization: State Key Laboratory for Cellular Stress Biology, Innovation Centre for Cell Signalling Network, School of Life Sciences, Xiamen University – sequence: 16 givenname: Yaying surname: Wu fullname: Wu, Yaying organization: State Key Laboratory for Cellular Stress Biology, Innovation Centre for Cell Signalling Network, School of Life Sciences, Xiamen University – sequence: 17 givenname: Zheni orcidid: 0000-0001-7926-0259 surname: Xu fullname: Xu, Zheni organization: State Key Laboratory for Cellular Stress Biology, Innovation Centre for Cell Signalling Network, School of Life Sciences, Xiamen University – sequence: 18 givenname: Junjie surname: Chen fullname: Chen, Junjie organization: Analysis and Measurement Centre, School of Pharmaceutical Sciences, Xiamen University – sequence: 19 givenname: Yong surname: Yu fullname: Yu, Yong organization: State Key Laboratory for Cellular Stress Biology, Innovation Centre for Cell Signalling Network, School of Life Sciences, Xiamen University – sequence: 20 givenname: Xi surname: Huang fullname: Huang, Xi organization: State Key Laboratory for Cellular Stress Biology, Innovation Centre for Cell Signalling Network, School of Life Sciences, Xiamen University – sequence: 21 givenname: Ying surname: He fullname: He, Ying organization: State Key Laboratory for Cellular Stress Biology, Innovation Centre for Cell Signalling Network, School of Life Sciences, Xiamen University – sequence: 22 givenname: Luming orcidid: 0000-0002-9417-4356 surname: Yao fullname: Yao, Luming organization: State Key Laboratory for Cellular Stress Biology, Innovation Centre for Cell Signalling Network, School of Life Sciences, Xiamen University – sequence: 23 givenname: Lei surname: Zhang fullname: Zhang, Lei organization: State Key Laboratory for Cellular Stress Biology, Innovation Centre for Cell Signalling Network, School of Life Sciences, Xiamen University – sequence: 24 givenname: Mingxia orcidid: 0000-0002-1858-5655 surname: Zhu fullname: Zhu, Mingxia organization: State Key Laboratory for Cellular Stress Biology, Innovation Centre for Cell Signalling Network, School of Life Sciences, Xiamen University – sequence: 25 givenname: Wen surname: Wang fullname: Wang, Wen organization: CAS Key Laboratory of Separation Science for Analytical Chemistry, Dalian Institute of Chemical Physics, Chinese Academy of Sciences – sequence: 26 givenname: Zhi-Chao surname: Wang fullname: Wang, Zhi-Chao organization: CAS Key Laboratory of Separation Science for Analytical Chemistry, Dalian Institute of Chemical Physics, Chinese Academy of Sciences – sequence: 27 givenname: Mingliang surname: Zhang fullname: Zhang, Mingliang organization: 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 – sequence: 28 givenname: Yuqian surname: Bao fullname: Bao, Yuqian organization: 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 – sequence: 29 givenname: Weiping orcidid: 0000-0002-6244-2168 surname: Jia fullname: Jia, Weiping organization: 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 – sequence: 30 givenname: Shu-Yong orcidid: 0000-0002-4419-1713 surname: Lin fullname: Lin, Shu-Yong organization: State Key Laboratory for Cellular Stress Biology, Innovation Centre for Cell Signalling Network, School of Life Sciences, Xiamen University – sequence: 31 givenname: Zhiyun surname: Ye fullname: Ye, Zhiyun organization: State Key Laboratory for Cellular Stress Biology, Innovation Centre for Cell Signalling Network, School of Life Sciences, Xiamen University – sequence: 32 givenname: Hai-Long orcidid: 0000-0001-7451-0386 surname: Piao fullname: Piao, Hai-Long organization: CAS Key Laboratory of Separation Science for Analytical Chemistry, Dalian Institute of Chemical Physics, Chinese Academy of Sciences – sequence: 33 givenname: Xianming orcidid: 0000-0002-9354-5864 surname: Deng fullname: Deng, Xianming email: xmdeng@xmu.edu.cn organization: State Key Laboratory for Cellular Stress Biology, Innovation Centre for Cell Signalling Network, School of Life Sciences, Xiamen University – sequence: 34 givenname: Chen-Song orcidid: 0000-0001-5218-0101 surname: Zhang fullname: Zhang, Chen-Song email: cszhang@xmu.edu.cn organization: State Key Laboratory for Cellular Stress Biology, Innovation Centre for Cell Signalling Network, School of Life Sciences, Xiamen University – sequence: 35 givenname: Sheng-Cai orcidid: 0000-0003-1993-8376 surname: Lin fullname: Lin, Sheng-Cai email: linsc@xmu.edu.cn organization: State Key Laboratory for Cellular Stress Biology, Innovation Centre for Cell Signalling Network, School of Life Sciences, Xiamen University |
| BackLink | https://www.ncbi.nlm.nih.gov/pubmed/35197629$$D View this record in MEDLINE/PubMed |
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| Copyright | The Author(s) 2022 2022. The Author(s). Copyright Nature Publishing Group Mar 3, 2022 |
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. For clinical doses of... Metformin, the most prescribed antidiabetic medicine, has shown other benefits such as anti-ageing and anticancer effects 1–4 . For clinical doses of... Metformin, the most prescribed antidiabetic medicine, has shown other benefits such as anti-ageing and anticancer effects . For clinical doses of metformin,... Metformin, the most prescribed antidiabetic medicine, has shown other benefits such as anti-ageing and anticancer effects1-4. For clinical doses of metformin,... Metformin, the most prescribed antidiabetic medicine, has shown other benefits such as anti-ageing and anticancer effects1–4. For clinical doses of metformin,... |
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| Title | Low-dose metformin targets the lysosomal AMPK pathway through PEN2 |
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