PXD030090-2

PXD030090 is an original dataset announced via ProteomeXchange.

Title	Low-dose metformin targets the lysosome-AMPK pathway through PEN2
Description	Metformin 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.
HostingRepository	iProX
AnnounceDate	2021-12-01
AnnouncementXML	Submission_2022-02-24_18:42:46.323.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	ChenSong Zhang
SpeciesList	scientific name: Homo sapiens; NCBI TaxID: 9606; scientific name: Mus musculus; NCBI TaxID: 10090;
ModificationList	No PTMs are included in the dataset
Instrument	timsTOF Pro; TripleTOF 5600; Orbitrap Fusion Lumos

Revision	Datetime	Status	ChangeLog Entry
0	2021-12-01 19:22:05	ID requested
1	2021-12-01 19:22:34	announced
⏵ 2	2022-02-24 18:42:47	announced	2022-02-25: Update publication information.

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]

submitter keyword: metformin, AMPK, PEN2, ATP6AP1

ShengCai Lin
contact affiliation	Xiamen University
contact email	linsc@xmu.edu.cn
lab head
ChenSong Zhang
contact affiliation	Xiamen University
contact email	cszhang@xmu.edu.cn
dataset submitter

iProX dataset URI