| First Author | Ma T | Year | 2022 |
| Journal | Nature | Volume | 603 |
| Issue | 7899 | Pages | 159-165 |
| PubMed ID | 35197629 | Mgi Jnum | J:342797 |
| Mgi Id | MGI:7294126 | Doi | 10.1038/s41586-022-04431-8 |
| Citation | Ma T, et al. (2022) Low-dose metformin targets the lysosomal AMPK pathway through PEN2. Nature 603(7899):159-165 |
| abstractText | 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 gamma-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. |
