Caspase Independent Apoptosis: New Insights and Current Perspectives

Apoptosis is an evolutionarily conserved cell death modality that regularly maintains a harmonious homeostasis between cellular genesis and demise. Caspases are a unique class of cysteine proteases that exist as inactive zymogens within the cells and follow a sequential cascade of catalytic activation for onset of apoptosis induction. Although the importance of caspases in apoptosis has received huge attention, considerable focus on caspase-independent mammalian cell death needs to be elucidated. The phenomenon of caspase-independent cell death (CICD) in mammals narrates a process of “determination” between cell survival and death upstream of caspase activation or without reliance on a caspase trigger, primarily in case of permeabilization of the outer mitochondrial membrane. Often, cells undergoing CICD exhibit distinctive features, such as the formation of large cytoplasmic vacuoles, accumulation of autophagosomes, peripheral condensation of the nuclei, etc. However, unlike apoptosis where cells exhibit a relatively uniform and consistent set of characteristics, cells undergoing CICD can manifest a wide range of variable traits depending on varied factors such as the initial stimulus and the type of cells involved. This chapter aims to explore the molecular mechanisms of CICD and its potential roles in the onset of various diseases from a pathophysiological perspective.