Interplay of energy metabolism and autophagy

Abstract

Macroautophagy/autophagy, is widely recognized for its crucial role in enabling cell survival and maintaining cellular energy homeostasis during starvation or energy stress. Its regulation is intricately linked to cellular energy status. In this review, covering yeast, mammals, and plants, we aim to provide a comprehensive overview of the understanding of the roles and mechanisms of carbon- or glucose-deprivation related autophagy, showing how cells effectively respond to such challenges for survival. Further investigation is needed to determine the specific degraded substrates by autophagy during glucose or energy deprivation and the diverse roles and mechanisms during varying durations of energy starvation.Abbreviations: ADP: adenosine diphosphate; AMP: adenosine monophosphate; AMPK: AMP-activated protein kinase; ATG: autophagy related; ATP: adenosine triphosphate; ER: endoplasmic reticulum; ESCRT: endosomal sorting complex required for transport; GAPDH: glyceraldehyde-3-phosphate dehydrogenase; GD: glucose deprivation; GFP: green fluorescent protein; GTPases: guanosine triphosphatases; HK2: hexokinase 2; K phaffii: Komagataella phaffii; LD: lipid droplet; MAP1LC3/LC3: microtubule-associated protein1 light chain 3; MAPK: mitogen-activated protein kinase; Mec1: mitosis entry checkpoint 1; MTOR: mechanistic target of rapamycin kinase; NAD (+): nicotinamide adenine dinucleotide; OGD: oxygen and glucose deprivation; PAS: phagophore assembly site; PCD: programmed cell death; PtdIns3K: class III phosphatidylinositol 3-kinase; PtdIns3P: phosphatidylinositol-3-phosphate; ROS: reactive oxygen species; S. cerevisiae: Saccharomyces cerevisiae; SIRT1: sirtuin 1; Snf1: sucrose non-fermenting 1; STK11/LKB1: serine/threonine kinase 11; TFEB: transcription factor EB; TORC1: target of rapamycin complex 1; ULK1: unc-51 like kinase 1; Vps27: vacuolar protein sorting 27; Vps4: vacuolar protein sorting 4.

Keywords: AMPK; Snf1; autophagy; carbon starvation; energy metabolism; glucose starvation.

Figure 1.

Molecular mechanisms underlying macroautophagy and lipophagy induced by glucose deprivation (GD) in yeasts. Under glucose starvation, Ggc1 recruits Mec1 to the mitochondrial surface, leading to the formation of Mec1 puncta in a process that requires ROS. Mitochondrial fusion facilitates the binding between Snf1 and Mec1, resulting in Mec1 phosphorylation by Snf1. The phosphorylation of Mec1 promotes the recruitment of Atg1 to the mitochondria. Atg11 mediates the interaction of Snf1 and Atg1. The Snf1-Mec1-Atg1 complex is necessary for maintaining mitochondrial respiration. In turn, mitochondrial respiration is required for glucose starvation-induced Mec1 phosphorylation. Atg11 also mediates the association of Atg17 with Atg29-Atg31 and facilitates the recruitment of Atg9 vesicles to the PAS. Additionally, glucose starvation suppresses the activity of Ryh1, a small GTPase, inhibiting TORC2 and enhancing autophagy. Glucose deprivation also enhances the activity of Sty1, a MAPK family member, to upregulate autophagy-related genes expression. During lipophagy, Snf1-dependant translocation of Atg14 from the ER to the vacuole is critical for the formation of the raft-like domain, which contains PtdIns4P. NPC/Niemann Pick type C proteins facilitate the expansion of the raft-like domain. Specifically in glucose starvation, Cue5, a selective aggrephagy receptor in K. phaffii, is degraded together with lipid droplets (LD, spherical organelles containing lipids) via autophagy.

Figure 2.

Schematic diagram illustrating the process of autophagy initiation in mammalian cells in response to glucose starvation. When glucose is deprived, the decrease in cellular AMP or ADP levels is detected by AMPK. A decrease in fructose-1,6-bisphosphate (FBP), a metabolic intermediate of glycolysis, can activate AMPK to induce autophagy. In addition, an increase in ammonia produced by amino acid catabolism can also trigger autophagy initiation. Activated AMPK can suppress MTORC1 via phosphorylating RPTOR (a component of MTORC1) and activating TSC2 (suppressor of MTORC1). Independent of AMPK, MTORC1 can also be inhibited by enhanced interaction with DEPTOR and HK2 under glucose starvation. PtdIns3P (a phospholipid in cell membranes) is required to initiate autophagy under nitrogen starvation, while PtdIns5P can substitute for PtdIns3P in glucose deprivation-induced autophagy. PtdIns5P mediates the recruitment of WIPI2 and ZFYVE1 to phagophores, maintaining ATG12–ATG5 conjugation and autophagy. Dashed lines indicate that the intermediate mechanisms are unclear.