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 starvation⁶. We synthesize a photoactive metformin probe and identify PEN2, a subunit of γ-secretase⁷, 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-ATPase⁸

SUBMITTER: Ma T 

PROVIDER: S-EPMC8891018 | biostudies-literature | 2022 Mar

REPOSITORIES: biostudies-literature