Vacuolar H+-ATPase–presenilin enhancer 2 complex (v-ATPase–PEN2 complex) (v-ATPase–PEN2 complex)

The Vacuolar H+-ATPase–lysosomal PEN2 complex is a specialized protein assembly located on the lysosomal membrane that serves as a key metabolic sensor. It comprises the vacuolar-type H+-ATPase (v-ATPase), an essential proton pump, and Presenilin enhancer 2 (PEN2), a subunit of the gamma-secretase complex that also functions as a direct receptor for the drug metformin (Ma et al., 2022, Nature). Under low glucose conditions or in the presence of metformin, PEN2 binds to the ATP6AP1 subunit of the v-ATPase, initiating a signaling cascade that recruits the AXIN-LKB1 complex to the lysosome. This recruitment facilitates the activation of AMP-activated protein kinase (AMPK), a master regulator of energy metabolism, without requiring an increase in the cellular AMP/ATP ratio (Zhang et al., 2014, Cell Metabolism). By modulating this complex, metformin exerts its glucose-lowering and potentially anti-aging and anti-cancer effects. This target represents a significant shift in the understanding of metformin's pharmacology, moving from mitochondrial inhibition to a specific lysosomal signaling pathway (UniProt Q9NZ42).

Other names

PEN2–v-ATPase complexMetformin–PEN2–v-ATPase complexLysosomal glucose-sensing complex

Metformin binds to PEN2, which then interacts with the ATP6AP1 subunit of the v-ATPase to recruit the AXIN-LKB1 complex, leading to the activation of AMPK.