Presenilin enhancer 2-associated AMP-activated protein kinase activation complex (PEN2-AMPK complex) (PEN2-AMPK complex)

The PEN2-associated AMPK activation complex is a multi-protein signaling hub located on the lysosomal surface that mediates the glucose-sensing function of AMP-activated protein kinase (AMPK). This complex is primarily composed of Presenilin enhancer 2 (PEN2), a component of the gamma-secretase complex, and the ATP6AP1 subunit of the vacuolar ATPase (v-ATPase) (Ma et al., 2022, Nature). Under conditions of glucose deprivation, PEN2 interacts with ATP6AP1 to facilitate the recruitment of AMPK to the lysosome, where it is phosphorylated and activated by the upstream kinase LKB1. Notably, the widely used anti-diabetic drug metformin has been identified as a direct ligand for PEN2, triggering the formation of this complex even in the presence of glucose, thereby mimicking a low-energy state. This pathway represents a distinct, lysosome-dependent mechanism for AMPK activation that operates alongside the classical AMP-dependent pathway. Targeting the PEN2-AMPK axis offers significant therapeutic potential for metabolic disorders, including type 2 diabetes and obesity, and its modulation is linked to the anti-aging and anti-tumor effects of metformin (Zhang et al., 2017, Nature).

Other names

PEN2-ATP6AP1-AMPK complexLysosomal glucose-sensing AMPK complexPEN2-v-ATPase-AMPK complex

Metformin binds directly to PEN2, which then interacts with the v-ATPase subunit ATP6AP1 to facilitate the recruitment and activation of AMPK on the lysosomal surface, mimicking a low-glucose state.