Abstract
While cell death is a normal and essential component of development and homeostasis, dysregulation of this process underlies most human diseases, including cancer, autoimmunity and neurodegeneration. The best characterized mechanism for cell death is apoptosis, although some cells die by a distinct process known as autophagy-dependent cell death (ADCD). Autophagy is mediated by the formation of double membrane vesicles that contain protein aggregates, damaged organelles like mitochondria, and bulk cytoplasm, which then fuse with lysosomes to degrade and recycle their contents. Autophagy is typically viewed as an adaptive process that allows cells to survive stresses like nutrient deprivation, although increasing evidence suggests that it may also mediate cell death during development and pathogenesis. An aggressive form of autophagy termed autosis has been described in cells following either ischemia/reperfusion injury or in response to autophagy-inducing proteins like Tat-Beclin 1. Despite an extensive literature on autophagic cell death in a variety of contexts, there are still fundamental gaps in our understanding of this process. As examples: Does autophagy directly kill cells and if so how? Is ADCD activated concurrently when cells are triggered to die via apoptosis? And is ADCD essentially a more protracted version of autosis or a distinct pathway? The goal of this mini-review is to summarize the field and to identify some of the major gaps in our knowledge. Understanding the molecular mechanisms that mediate ADCD will not only provide new insights into development, they may facilitate the creation of better tools for both the diagnostics and treatment of disease.
Highlights
The term programmed cell death (PCD) was coined by Lockshin and Williams (1965) to describe the precisely timed loss of skeletal muscles at the end of metamorphosis in moths
In order to determine that cells die via autophagydependent cell death (ADCD), it has been proposed that three criteria must be met: (1) other forms of cell death have been excluded; (2) there is an increase in autophagic flux; and (3) genetic or pharmacological blockade of autophagy rescues the cell (Shen and Codogno, 2011; Galluzzi et al, 2018)
In a high throughput screen, it was found that inhibitors of Na+, K+ adenosine triphosphatase (ATPase) like the cardiac glycosides ouabain and digoxin can inhibit autosis, which is diagnostic for autosis (Liu et al, 2013; Nah et al, 2020)
Summary
The term programmed cell death (PCD) was coined by Lockshin and Williams (1965) to describe the precisely timed loss of skeletal muscles at the end of metamorphosis in moths. Cell death can target tissues that have served an important function at one stage of development but are no longer needed at a later stage, such as regression of the tadpole tail during amphibian metamorphosis (Smith and Tata, 1976). These “surplus” tissues represent valuable reservoirs of macromolecules that can be used to support metabolism and development. PCD is still an acceptable term for those deaths that occur as a normal component of development
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