Low-dose metformin targets the lysosomal AMPK pathway through PEN2
Open accessAbstract
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.
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The pro-inflammatory cytokine network is one potential anti-aging target, using anti-inflammation drugs such as metformin, aspirin, rapamycin, and ibuprofen.
“Recent studies have demonstrated that the pro-inflammatory cytokine network is one potential anti-aging target, using anti-inflammation drugs such as metformin, aspirin, rapamycin, and ibuprofen.”
From Inflammation and aging: signaling pathways and intervention therapies (2023) · cites this paper as [339]
The Main section says metformin can extend lifespan and health span in nematodes and mice, and the Discussion reports lifespan extension through the PEN2–ATP6AP1–AMPK pathway. The paper does not identify the pro-inflammatory cytokine network as the target of that effect or support the claim about aspirin, rapamycin and ibuprofen as anti-aging drugs. (LLM, conf=0.88)
Experimental — accuracy not yet measuredMetformin can reduce chronic inflammation and improve healthy mid-life aging by acting on targets such as IKK/NF-κB in patients with Type 2 diabetes, as well as GPX7/NRF2 and PEN2.
“For example, metformin can reduce chronic inflammation and improve healthy mid-life aging by acting on possible targets such as IKK/NF-κB in patients with Type 2 diabetes,337 as well as GPX7/NRF2338 and a recently found target, PEN2.339”
From Inflammation and aging: signaling pathways and intervention therapies (2023) · cites this paper as [339]
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“For example, metformin can reduce chronic inflammation and improve healthy mid-life aging by acting on possible targets such as IKK/NF-κB in patients with Type 2 diabetes,337 as well as GPX7/NRF2338 and a recently found target, PEN2.”
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- Authors
- Ma, T., Tian, X., Zhang, B., Li, M., Wang, Y., Yang, C., Wu, J., Wei, X., Qu, Q., Yu, Y., Long, S., Feng, J.-W., Li, C., Zhang, C., Xie, C., Wu, Y., Xu, Z., Chen, J., Yu, Y., Huang, X., He, Y., Yao, L., Zhang, L., Zhu, M., Wang, W., Wang, Z.-C., Zhang, M., Bao, Y., Jia, W., Lin, S.-Y., Ye, Z., Piao, H.-L., Deng, X., Zhang, C.-S., & Lin, S.-C.
- Affiliations
- Xiamen University (CN)
- Dalian Institute of Chemical Physics (CN)
- Shanghai Jiao Tong University (CN)
- Corresponding author
- Zhang, Cixiong
- Deng, Xianming
- Zhang, Chen-Song
- ORCID
- Venue
- Nature
- Published
- 2022-02-23
- Volume
- 603
- Issue
- 7899
- Pages
- 159-165
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- PMC
- PMC8891018
- OpenAlex
- W4213415596
- Cited by
- 644
- References
- 64
- Citations by year
- 2026: 137 · 2025: 171 · 2024: 155 · 2023: 113 · 2022: 68
- FWCI
- 41.67
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Locations
- Nature (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Metabolism, Diabetes, and Cancer
- Health Sciences › Medicine › Epidemiology › Autophagy in Disease and Therapy
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › ATP Synthase and ATPases Research
- Keywords
- metformin, AMPK activation, Pen-2, V-ATPase, ATP6AP1, AMPK-independent mechanism, glucose-lowering effect, lifespan extension, Caenorhabditis elegans, drug target identification
- MeSH terms
- Adenosine Triphosphatases, Animals, Diabetes Mellitus, Glucose, Humans, Hypoglycemic Agents, Lysosomes, Membrane Proteins, Metformin, Caenorhabditis elegans, Vacuolar Proton-Translocating ATPases, Amyloid Precursor Protein Secretases, AMP-Activated Protein Kinases
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