Presenilin enhancer 2–ATPase H+ transporting accessory protein 1 lysosomal complex (PEN2–ATP6AP1)

The PEN2–ATP6AP1 lysosomal complex is a molecular assembly that plays a pivotal role in cellular energy sensing and metabolic regulation. It is composed of Presenilin enhancer 2 (PEN2), traditionally known as a subunit of the gamma-secretase complex, and ATPase H+ transporting accessory protein 1 (ATP6AP1), a component of the vacuolar-type H+-ATPase (v-ATPase) (Ma et al., 2022, Nature). This complex was recently identified as the direct molecular target for the glucose-lowering drug metformin at low, clinically relevant concentrations. Metformin binds directly to PEN2, which then facilitates an interaction with ATP6AP1 on the lysosomal membrane (Ma et al., 2022, Nature). This interaction inhibits the v-ATPase, leading to the recruitment of the AXIN-LKB1 complex and the subsequent phosphorylation and activation of AMP-activated protein kinase (AMPK) (Zhang et al., 2023, Cell Metabolism). Unlike the mitochondrial mechanism of metformin, this lysosomal pathway does not require an increase in the cellular AMP/ATP ratio, making the PEN2–ATP6AP1 complex a central hub for metformin's therapeutic action in type 2 diabetes. Beyond diabetes, the complex is a subject of intense research regarding its role in longevity and cancer due to its ability to modulate the AMPK-mTORC1 signaling axis (UniProt, 2024).

Other names

PEN2-ATP6AP1 complexMetformin-PEN2-v-ATPase axisLysosomal AMPK-activating complexPSENEN-ATP6AP1 complex

Metformin binds directly to the PEN2 subunit, which then facilitates a physical interaction with the ATP6AP1 subunit of the v-ATPase complex. This interaction inhibits v-ATPase activity, triggering the recruitment of the AXIN-LKB1 complex to the lysosomal surface, where LKB1 phosphorylates and activates AMP-activated protein kinase (AMPK) (Ma et al., 2022, Nature).