AMPK: Sensing Glucose as well as Cellular Energy Status

Abstract

Mammalian AMPK is known to be activated by falling cellular energy status, signaled by rising AMP/ATP and ADP/ATP ratios. We review recent information about how this occurs but also discuss new studies suggesting that AMPK is able to sense glucose availability independently of changes in adenine nucleotides. The glycolytic intermediate fructose-1,6-bisphosphate (FBP) is sensed by aldolase, which binds to the v-ATPase on the lysosomal surface. In the absence of FBP, interactions between aldolase and the v-ATPase are altered, allowing formation of an AXIN-based AMPK-activation complex containing the v-ATPase, Ragulator, AXIN, LKB1, and AMPK, causing increased Thr172 phosphorylation and AMPK activation. This nutrient-sensing mechanism activates AMPK but also primes it for further activation if cellular energy status subsequently falls. Glucose sensing at the lysosome, in which AMPK and other components of the activation complex act antagonistically with another key nutrient sensor, mTORC1, may have been one of the ancestral roles of AMPK.

Hallmarks of Brain Aging: Adaptive and Pathological Modification by Metabolic States

“…Action potentials and synaptic activity are mediated by Na + and Ca 2+ influx through plasma membrane channels, followed by their subsequent extrusion by membrane ion-motive ATPases (Na + and Ca 2+ “pumps”); the attendant consumption of ATP increases the AMP/ATP ratio, resulting in the activation of AMP-activated protein kinase (AMPK). AMPK then phosphorylates and thereby regulates the activities of proteins involved in energy metabolism (glucose transporters and the mTOR pathway), autophagy, and neuronal excitability (Weisová et al, 2009; Ikematsu et al, 2011; Lin and Hardie, 2018; Shah et al, 2017). Calcium is an important signal mediating cellular stress adaptation; Ca 2+ binds to the protein calmodulin, resulting in the activation of kinases that promote the activation of transcription factors including CREB and nuclear factor κB (NF-κB) (Cohen et al, 2015; Saura and Cardinaux, 2017; Snow et al, 2014).…”

Vacuolar ATPase as a potential therapeutic target and mediator of treatment resistance in cancer

“…Although AMPK is classically activated in response to rising AMP/ATP ratios, recent studies have demonstrated that V‐ATPase plays a role in AMP‐independent AMPK activation. Thus, binding of aldolase to V‐ATPase in the absence of the glycolytic intermediate fructose‐1,6‐bisphosphate results in AMPK activation 10, 11…”

Is TAK1 a Direct Upstream Kinase of AMPK?

“…In addition, there is a growing base of reviews focusing on different aspects of AMPK, such as the functions of AMPK in various tissues, or (patho-)physiological contexts (e.g., [1,2,3,4]). For AMPK novices, Hardie provides an excellent overview (e.g., [5,6,7,8]). In a nutshell, AMPK is an energy-sensing kinase that functions to maintain cellular and whole body energy balance [9].…”