The AMPK signalling pathway coordinates cell growth, autophagy and metabolism

Abstract

One of the central regulators of cellular and organismal metabolism in eukaryotes is the AMP-activated protein kinase (AMPK), which is activated when intracellular ATP levels lower. AMPK plays critical roles in regulating growth and reprogramming metabolism, and recently has been connected to cellular processes including autophagy and cell polarity. We review here a number of recent breakthroughs in the mechanistic understanding of AMPK function, focusing on a number of new identified downstream effectors of AMPK.

Increasing autophagy and blocking Nrf2 suppress laminopathy‐induced age‐dependent cardiac dysfunction and shortened lifespan

“…Our findings are consistent with studies in mouse laminopathy models in which rapamycin and temsirolimus had beneficial effects on heart and skeletal muscle through inhibition of AKT/mTOR signaling (Choi et al., 2012; Ramos et al., 2012). Our findings are depicted in a model (Figure 7) in which cytoplasmic aggregation of mutant LamC results in upregulation of p62, which in turn inhibits autophagy via activation of TOR and inactivation of AMPK (Mihaylova & Shaw, 2011). AMPK inactivation leads to the activation of PI3K/Akt/mTOR pathway and inhibition of autophagy (Porta, Paglino & Mosca, 2014) Atg1 OE promoted clearance of the LamC aggregates and restored proteostasis in these Drosophila models.…”

“…Continued expression of antioxidant genes results in the disruption of redox homeostasis, defective mitochondria, and dysregulation of energy homeostasis/energy sensor such as AMPK and its downstream targets. Simultaneously, upregulation of Ref(2)P (p62) causes inhibition of autophagy via activation of TOR, which leads to the inactivation of AMPK (Mihaylova & Shaw, 2011). AMPK inactivation in combination with activation of the TOR pathway causes cellular and metabolic stress that leads to cardiomyopathy.…”

Antagonizing peroxisome proliferator‐activated receptor γ facilitates M1‐to‐M2 shift of microglia by enhancing autophagy via the LKB1–AMPK signaling pathway

“…Accordingly, the application of the PPARγ antagonist induced the phosphorylation of LKB1 (Figure 3e–h). LKB1 binds with pseudokinase Ste20‐related adaptor (STRAD) and scaffolding‐like adaptor protein mouse protein 25 (MO25) to form a complex, and it subsequently achieves full activation (Lin et al., 2015; Mihaylova & Shaw, 2011). We further demonstrated the impact of PPARγ antagonist on LKB1 activation using a co‐immunoprecipitation (Co‐IP) assay.…”

AMPK activation protects cells from oxidative stress‐induced senescence via autophagic flux restoration and intracellular NAD + elevation

“…AMPK signaling also activates autophagy. The most commonly described mechanism underlying the effects of AMPK on autophagy is suppression of the mTORC1 pathway (Mihaylova & Shaw, 2011; Salminen & Kaarniranta, 2012). Several pharmacological activators of AMPK, such as metformin and berberine, have been characterized, and their potential for the treatment of metabolic, neurodegenerative and other aging‐related diseases is well recognized (Steinberg & Kemp, 2009; Mo et al ., 2014).…”