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PXD030090-1

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.
HostingRepositoryiProX
AnnounceDate2021-12-01
AnnouncementXMLSubmission_2021-12-01_19:22:33.858.xml
DigitalObjectIdentifier
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
Dataset with its publication pending
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
iProX dataset URI