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Metformin, the most prescribed antidiabetic medicine, has shown other benefits such as anti-ageing and anticancer effects^{, , –}. For clinical doses of metformin, AMP-activated protein kinase (AMPK) has a major role in its mechanism of action^,; 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. We synthesize a photoactive metformin probe and identify PEN2, a subunit of γ-secretase, 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, 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 …