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PXD030090 is an original dataset announced via ProteomeXchange.

Dataset Summary
TitleLow-dose metformin targets the lysosome-AMPK pathway through PEN2
DescriptionMetformin is the most prescribed anti-diabetic medicine, and has also been shown to have other various benefits, such as anti-aging and anti-cancer effects. For clinical doses of metformin, it is known that AMPK plays a major role; however, the direct molecular target of metformin remains unclear. Here, we found that clinically relevant concentrations of metformin inhibits the lysosomal proton pump (v-ATPase), which has been shown to be a central node for AMPK activation upon glucose starvation. We synthesised a photoactive metformin probe, and identified that PEN2, a subunit of γ-secretases, is a binding partner of metformin with KD at micromolar levels. Metformin-bound PEN2 then forms a complex with ATP6AP1, a subunit of the v-ATPase, leading to inhibition of v-ATPase and activation of AMPK without affecting cellular AMP levels. Knockout of PEN2, or re-introduction of a PEN2 mutant that fails to bind ATP6AP1, blunts AMPK activation. In vivo, liver-specific knockout of PEN2 abolishes metformin-mediated reduction of hepatic fat content, and intestine-specific knockout of PEN2 impairs its glucose-lowering effects. Furthermore, knockdown of PEN2 in Caenorhabditis elegans abrogates metformin-induced extension of lifespan. Together, these findings reveal that metformin binds to PEN2, initiating a signalling route that intersects, via ATP6AP1, the lysosomal glucose-sensing pathway for AMPK activation, ensuring that metformin manifests therapeutic benefits without significant drawbacks in patients.
ReviewLevelPeer-reviewed dataset
DatasetOriginOriginal dataset
RepositorySupportUnsupported dataset by repository
PrimarySubmitterChenSong Zhang
SpeciesList scientific name: Homo sapiens; NCBI TaxID: 9606; scientific name: Mus musculus; NCBI TaxID: 10090;
ModificationListNo PTMs are included in the dataset
InstrumenttimsTOF Pro; TripleTOF 5600; Orbitrap Fusion Lumos
Dataset History
RevisionDatetimeStatusChangeLog Entry
02021-12-01 19:22:05ID requested
12021-12-01 19:22:34announced
22022-02-24 18:42:47announced2022-02-25: Update publication information.
Publication List
Ma T, Tian X, Zhang B, Li M, Wang Y, Yang C, Wu J, Wei X, Qu Q, Yu Y, Long S, Feng JW, 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 ZC, Zhang M, Bao Y, Jia W, Lin SY, Ye Z, Piao HL, Deng X, Zhang CS, Lin SC, Low-dose metformin targets the lysosomal AMPK pathway through PEN2. Nature, 603(7899):159-165(2022) [pubmed]
Keyword List
submitter keyword: metformin, AMPK, PEN2, ATP6AP1
Contact List
ShengCai Lin
contact affiliationXiamen University
contact emaillinsc@xmu.edu.cn
lab head
ChenSong Zhang
contact affiliationXiamen University
contact emailcszhang@xmu.edu.cn
dataset submitter
Full Dataset Link List
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