Till Death Do Us Part: The Marriage of Autophagy and Apoptosis

Abstract

Autophagy is a widely conserved catabolic process that is necessary for maintaining cellular homeostasis under normal physiological conditions and driving the cell to switch back to this status quo under times of starvation, hypoxia, and oxidative stress. The potential similarities and differences between basal autophagy and stimulus-induced autophagy are still largely unknown. Both act by clearing aberrant or unnecessary cytoplasmic material, such as misfolded proteins, supernumerary and defective organelles. The relationship between reactive oxygen species (ROS) and autophagy is complex. Cellular ROS is predominantly derived from mitochondria. Autophagy is triggered by this event, and by clearing the defective organelles effectively, it lowers cellular ROS thereby restoring cellular homeostasis. However, if cellular homeostasis cannot be reached, the cells can switch back and choose a regulated cell death response. Intriguingly, the autophagic and cell death machines both respond to the same stresses and share key regulatory proteins, suggesting that the pathways are intricately connected. Here, the intersection between autophagy and apoptosis is discussed with a particular focus on the role ROS plays.

Figure 1

Schematic overview the five stages of the autophagy pathway. The execution point of where known pharmacological inhibitors act are written in purple. See text for details.

Figure 2

Diagram showing the closely linked relationship between ROS levels, autophagy, and apoptosis. See text for details.

Figure 3

Schematic illustration of the mechanism involved in reactive oxygen species (ROS) formation and elimination. Endogenous forms of ROS arise from NADPH oxidase (NOX) as well as the organelles shown. The cytosolic superoxide (O₂⁻) is converted into hydrogen peroxide (H₂O₂) by superoxide dismutase (SOD). H₂O₂ has three fates. It can be detoxified to water by glutathione peroxidase (GPX) peroxiredoxin (PRx), thioredoxin (TRX), and catalase (CAT). The reduced form of glutathione (GSH) promotes this reaction whereas oxidation to glutathione disulfide GSSH results in intracellular redox. H₂O₂ can be converted to the cytotoxic hydroxyl radical (OH⁻) via the Fenton reaction resulting in irreversible damage to lipids, proteins, and DNA. Lastly, H₂O₂ can also be used as a signaling molecule by oxidizing critical thiols within proteins to regulate numerous biological processes.

Figure 4

Diagram depicting the genetic relationship between ROS and autophagy initiation. The dotted lines represent an indirect relationship.

Figure 5

Diagram showing the intricate relationship between autophagy and the extrinsic and intrinsic apoptotic pathways. See text for details.