Balancing nutrient and energy demand and supply via autophagy

Abstract

Maintaining nutrient and energy homeostasis is crucial for the survival and function of cells and organisms in response to environmental stress. Cells have evolved a stress-induced catabolic pathway, termed autophagy, to adapt to stress conditions such as starvation. During autophagy, damaged or non-essential cellular structures are broken down in lysosomes, and the resulting metabolites are reused for core biosynthetic processes or energy production. Recent studies have revealed that autophagy can target and degrade different types of nutrient stores and produce a variety of metabolites and fuels, including amino acids, nucleotides, lipids and carbohydrates. Here, we will focus on how autophagy functions to balance cellular nutrient and energy demand and supply - specifically, how energy deprivation switches on autophagic catabolism, how autophagy halts anabolism by degrading the protein synthesis machinery, and how bulk and selective autophagy-derived metabolites recycle and feed into a variety of bioenergetic and anabolic pathways during stress conditions. Recent new insights and progress in these areas provide a better understanding of how resource mobilization and reallocation sustain essential metabolic and anabolic activities under unfavorable conditions.

Figure 1.. Schematic illustration of autophagic metabolism of proteins, nucleic acids, carbohydrates and lipids, and their crosstalk in energy production.

The amount of energy produced per glucose molecule (or equivalent precusors) is: 2 ATPs from glycolysis, 2 ATPs from the tricarboxylic acid (TCA) cycle, and a maximum of 34 ATPs by the ATP synthase of the mitochondrial electron transport chain. Autophagy-generated energy is also dissipated as heat via mitochondrial UCP1 (Uncoupling protein 1). Communication among different nutrient metabolic pathways is highlighted by green arrows.

Figure 2.. mTORC1-mediated inhibition and AMPK-mediated activation of autophagy via nutrient-, growth factor-, and energy-sensing.

Amino acids activate Rag GTPases, and growth factors activate the Rheb GTPase. Active Rag GTPases (GTP-bound RagA/B and GDP-bound RagC/D) and the active Rheb GTPase (GTP-bound Rheb) synergistically recruit and activate mTORC1 on the lysosomal membrane. Active mTORC1 phosphorylates and inhibits the autophagy-initiating kinase ULK1 and the master transcriptional regulator of autophagy TFEB. By contrast, AMPK senses low glucose and ATP levels, and activates ULK1 and the downstream VPS34 PI3K complex to activate autophagy. Autophagy delivers a variety of substrates, including proteins, organelles (such as ribosomes and associated RNAs), lipid droplets (LDs), glycogen and iron storages, to the lysosome for degradation, which promotes nutrient mobilization for biosynthesis and energy production in response to nutrient and energy depletion. E, energy.

Figure 3.

Amino acids produced by non-selective bulk autophagy, or selective autophagy via a receptor that binds both Atg8/LC3 and the cargo, fulfill diverse functions of the cell.

Figure 4.. Degradation of ribosomal proteins, rRNA and ribosome-bound translating mRNA by ribophagy or autophagy-mediated RNA degradation.

Ribophagy and mRNA autophagy switches off protein synthesis and provides amino acids, nucleosides and bases, which can be further secreted outside of the cells. In yeast, deubiquitination of ribosomal proteins by the Ubp3-Bre5 ubiquitin protease is required for ribophagy. In mammalian cells, NUFIP1 serves as a ribophagy receptor that binds both LC3 and ribosomes. Autophagic sequestration of mRNAs requires Atg24-Atg20 or Atg24-Snx41 sorting nexin complexes in yeast. Ub, ubiquitin.

Figure 5.. Lipid mobilization by three types of autophagy.

(A) Fatty acids are produced by macrolipophagy (lipophagy) of LDs. It is unclear whether a receptor protein is required in macrolipophagy. (B) Chaperone-mediated autophagy degrades LD coating proteins PLIN2 and PLIN3, and increases the accessibility of the “naked” LDs to both cytosolic lipolysis and lipophagy. (C) Micro-lipophagy mediates the direct engulfment of LDs by the vacuole/lysosome at the liquid-ordered domain. ESCRT proteins, Atg39 and a number of autophagy proteins are involved in micro-lipophagy.

Figure 6.. Selective autophagic degradation of glycogen.

Glycogen is degraded in lysosomes by glycophagy via a receptor STBD1. Glucose is released for many anabolic functions. GAA, lysosomal acid α-glucosidase. LD, lipid droplet.