The Intricate Balance between Life and Death: ROS, Cathepsins, and Their Interplay in Cell Death and Autophagy

Abstract

Cellular survival hinges on a delicate balance between accumulating damages and repair mechanisms. In this intricate equilibrium, oxidants, currently considered physiological molecules, can compromise vital cellular components, ultimately triggering cell death. On the other hand, cells possess countermeasures, such as autophagy, which degrades and recycles damaged molecules and organelles, restoring homeostasis. Lysosomes and their enzymatic arsenal, including cathepsins, play critical roles in this balance, influencing the cell's fate toward either apoptosis and other mechanisms of regulated cell death or autophagy. However, the interplay between reactive oxygen species (ROS) and cathepsins in these life-or-death pathways transcends a simple cause-and-effect relationship. These elements directly and indirectly influence each other's activities, creating a complex web of interactions. This review delves into the inner workings of regulated cell death and autophagy, highlighting the pivotal role of ROS and cathepsins in these pathways and their intricate interplay.

Keywords: apoptosis; autophagy; cathepsins; cell death; oxidative stress; reactive oxygen species (ROS).

Figure 1

Oxidative stress and oxidative eustress within redox biology. Rearranged from [40].

Figure 2

Interplay between ROS and cathepsins in apoptosis.

Figure 3

Interplay between ROS and cathepsins in types of regulated cell death. The cellular proteins are released from the cell through protein pores in the cell membrane, which are indicated by black dots. Red dots indicate lipid peroxidation in cell membranes.

Figure 4

The role of LC3 proteins in selective autophagy. The figure illustrates the involvement of the LC3 subfamily of ATG8 proteins in different steps of selective autophagy. Reproduced with permission from [172].

Figure 5

Correlation between cathepsin D expression and autophagy in HeLa cells: (A) Western blotting analysis of HeLa cells expressing wildtype cathepsin D and cathepsin D D295N after treatment with 1 mM of H₂O₂ for 24 h. (B) Percentage of HeLa cells with autophagy vacuoles after H₂O₂ treatment. Data were obtained from confocal images of cells transfected with GFP-LC3 plasmid. +/− means HeLa cells with or without H₂O₂ treatment, * indicates the significance. Reproduced with permission from [188].

Figure 6

Correlation between ROS, cathepsin B (CTSB), and cathepsin L (CTSL) in regulating autophagy and apoptosis as a result of thioredoxin reductase inhibition. Reproduced with permission from [190].