Low-dose metformin targets the lysosomal AMPK pathway through PEN2

Abstract 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 γ-secretase 7 , as a binding partner of metformin with a dissociation constant at micromolar levels. Metformin-bound PEN2 forms a…