Lysosomal AMP-activated protein kinase activation complex (Lysosomal AMPK machinery)

The lysosomal AMP-activated protein kinase (AMPK) activation machinery is a specialized protein complex on the lysosomal surface that integrates nutrient sensing with energy metabolism (Zhang et al., 2016, Nature). It comprises the vacuolar H+-ATPase (v-ATPase), the Ragulator complex (LAMTOR), AXIN, and the liver kinase B1 (LKB1), which together act as a scaffold for AMPK activation (Lin & Hardie, 2018, Cell Metabolism). In the presence of low glucose, the v-ATPase-Ragulator complex undergoes a conformational change that promotes the recruitment of AXIN and LKB1, leading to the phosphorylation of AMPK at Thr172 (Zhang et al., 2014, Cell Metabolism). This lysosomal pathway allows the cell to respond to glucose levels independently of the cytosolic AMP/ATP ratio, making it a vital component of metabolic flexibility. Therapeutic targeting of this machinery is a major strategy for treating type 2 diabetes, obesity, and non-alcoholic fatty liver disease, as it enhances glucose uptake and fatty acid oxidation. Metformin, the most widely prescribed anti-diabetic drug, has been shown to exert its effects partially through this lysosomal mechanism by inhibiting the v-ATPase (Zhang et al., 2016). Additionally, this machinery plays a role in longevity and cancer by regulating autophagy and cell growth through the reciprocal inhibition of mTORC1.

Other names

Lysosomal glucose-sensing machineryAXIN-LKB1-AMPK complexv-ATPase-Ragulator-AXIN-LKB1 complexLysosomal AMPK-activation complex

Promotes the recruitment of LKB1 to the lysosomal surface via the AXIN-Ragulator scaffold to phosphorylate and activate AMPK in response to glucose deficiency.