Low-dose metformin targets the lysosomal AMPK pathway through PEN2

Article

关键词: ACTIVATED PROTEIN-KINASE;    HEPATIC GLUCONEOGENESIS;    PEPTIDE-1 SECRETION;    GLUCOSE-PRODUCTION;    V-ATPASE;    CELL;    MECHANISMS;    SUBUNIT;    COMPLEX;    PHOSPHORYLATION;   

DOI  :  10.1038/s41586-022-04431-8

来源: SCIE

【 摘 要 】

The molecular target of the antidiabetic medicine metformin is identified as PEN2, a subunit of gamma-secretases, and the PEN2-ATP6AP1 axis offers potential targets for screening for metformin substitutes. 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.

【 授权许可】

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