AMPK: Regulation of Metabolic Dynamics in the Context of Autophagy

Abstract

Eukaryotic cells have developed mechanisms that allow them to link growth and proliferation to the availability of energy and biomolecules. AMPK (adenosine monophosphate-activated protein kinase) is one of the most important molecular energy sensors in eukaryotic cells. AMPK activity is able to control a wide variety of metabolic processes connecting cellular metabolism with energy availability. Autophagy is an evolutionarily conserved catabolic pathway whose activity provides energy and basic building blocks for the synthesis of new biomolecules. Given the importance of autophagic degradation for energy production in situations of nutrient scarcity, it seems logical that eukaryotic cells have developed multiple molecular links between AMPK signaling and autophagy regulation. In this review, we will discuss the importance of AMPK activity for diverse aspects of cellular metabolism, and how AMPK modulates autophagic degradation and adapts it to cellular energetic status. We will explain how AMPK-mediated signaling is mechanistically involved in autophagy regulation both through specific phosphorylation of autophagy-relevant proteins or by indirectly impacting in the activity of additional autophagy regulators.

Analysis of SARS-CoV-2-controlled autophagy reveals spermidine, MK-2206, and niclosamide as putative antiviral therapeutics

“…The initiation of autophagy is a cumulative result of multiple protein and signaling cascades that are involved in the energy and nutrient sensing of cells ( 7, 11 ). The AMP-activated protein kinase (AMPK) and the mammalian target of rapamycin complex 1 (mTORC1) kinase are in continuous crosstalk with glucose and protein homeostasis respectively ( 13, 14 ). We monitored key proteins of the AMPK and mTORC1 pathways and their regulation/degradation by Western blot analyses after infection with SARS-CoV-2 ( Figure 2 ).…”

The crosstalk of NAD, ROS and autophagy in cellular health and ageing

“…sequestosome 1 (SQSTM1/ p62), is then responsible for spatially linking the ubiquitylated cargo, including long-lived or aggregated proteins, pathogens and organelles, to the growing autophagosome (Dikic and Elazar 2018;Johansen and Lamark 2019). The canonical pathway of starvation-induced autophagy was long thought to rely on phosphorylation cascades that are triggered by the loss of nutrient signalling and converge on a small number of regulating kinase complexes (Beurel et al 2015;Rabanal-Ruiz et al 2017;Tamargo-Gómez and Mariño 2018). These regulators then either lose function and thus release downstream autophagy components from an inhibitory state, or become activated and promote autophagy initiation.…”

MicroRNAs play an essential role in autophagy regulation in various disease phenotypes

“…ULK1 then phosphorylates itself and its partners, FIP200 and ATG13, leading to the activation of autophagy by the formation of the ULK‐ATG13‐ATG101‐FIP200 complex . (B): Along with the phosphoinositide 3‐kinase regulatory subunit 4, ATG14, and the scaffold protein Bcl2‐interacting protein 1, phosphatidylinositol 3‐kinase catalytic subunit type 3 forms the class III PI3K complex, which generates a membrane domain enriched in PtsIns3P and creates PI3P (phosphatidylinositol‐3‐phosphate) at the site of nucleation of the phagophore which leads to the binding of PI3P binding proteins, and the subsequent recruitment of proteins involved in “the ubiquitin‐like protein conjugation systems” to the isolation membrane . (C): ATG5 is a lysine residue forms a covalent conjugation with a C‐terminal glycine residue of ATG12 is catalyzed by E1‐like enzyme Atg7 and E2 like enzyme Atg10, forming an autophagosomal precursor.…”

“…8-11 (B): Along with the phosphoinositide 3-kinase regulatory subunit 4, ATG14, and the scaffold protein Bcl2-interacting protein 1, phosphatidylinositol 3-kinase catalytic subunit type 3 forms the class III PI3K complex, which generates a membrane domain enriched in PtsIns3P and creates PI3P (phosphatidylinositol-3-phosphate) at the site of nucleation of the phagophore which leads to the binding of PI3P binding proteins, and the subsequent recruitment of proteins involved in "the ubiquitin-like protein conjugation systems" to the isolation membrane. [12][13][14] (C): ATG5 is a lysine residue forms a covalent conjugation with a C-terminal glycine residue of ATG12 is catalyzed by E1-like enzyme Atg7 and E2 like enzyme Atg10, forming an autophagosomal precursor. Typically, the ATG5-ATG12-ATG16L1 complex forms the autophagosome membrane in two ways: by directly binding with the membrane or by involving in the LC3-PE conjugation pathway.…”