PXD030090-1

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_2021-12-01_19:22:33.858.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.

Dataset with its publication pending

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