Chapter Three - Autophagy in Cell Life and Cell Death

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Abstract

Macroautophagy (hereafter referred to as autophagy) is a process used by the cell to deliver cytoplasmic components to the lysosome for degradation. Autophagy is most often associated with cell survival, as it provides cells with molecular building blocks during periods of nutrient deprivation and also aids in the elimination of damaged organelles and protein aggregates. However, autophagy has also been implicated in cell death. Here, we review what is known about autophagy, its regulation, its role both in cell life and cell death, and what is known about autophagic cell death in vivo.

Introduction

Autophagy is an evolutionarily conserved, catabolic process whereby cellular contents are sequestered by a double-membrane vesicle termed the autophagosome and brought to the lysosome for degradation (Fig. 1). This multistep process is executed and regulated by autophagy-related (Atg) proteins that control the initiation of autophagy, elongation of the autophagosome, and completion of this process. Traditionally, autophagy is thought of as a cell survival mechanism, acting in response to cellular stressors as a method of cell quality control. Basal autophagy is used by the cell to remove, for example, damaged organelles, long-lived proteins, and protein aggregates. Cellular stressors such as pathogen infection, hypoxia, nutrient limitation, or reactive oxygen species (ROS) can also trigger autophagy.

Most studies have focused on the function of autophagy during cell survival that is triggered by starvation. However, autophagy has also been tightly linked to cell death processes, participating side by side with either apoptosis or other cell death pathways, or independently to kill the cell. Cell death associated with autophagy was termed “autophagic cell death” by the Nomenclature Committee on Cell Death (NCCD), a group consisting of leading researchers in the field of cell death research, which defines it as a process that is blocked by genetic interventions targeting at least two components of the molecular machinery of autophagy (Galluzzi et al., 2012). Additionally, the committee suggests that clonogenic survival assays should be used to demonstrate long-term protection against cell death with genetic inhibition of autophagy, avoiding conclusions based merely on altered kinetics of cell death. Such autophagic cell death was seen in several studies, such as in cell death induced by various chemotherapy drugs and in Drosophila tissue cell death during the developmental transition from a larva to an adult, also known as metamorphosis. Although there is mounting evidence supporting autophagic cell death to date, the role of this process in mammals in vivo is unclear.

Section snippets

Autophagy Genes

Autophagy is a multistep process that is genetically regulated by the Atg genes. Pioneering studies in the yeast Saccharomyces cerevisiae involving screens for mutants with defects in autophagic structures resulted in the identification of Atg genes (Tsukada & Ohsumi, 1993), most of which are conserved in mammals.

Autophagy is initiated with the formation of a preautophagosomal structure (PAS) which serves as the nucleation point for the formation of the isolation membrane (Suzuki et al., 2001).

Clearance of Damaged Organelles

Cellular homeostasis is dependent on the maintenance of both organelle integrity and number in the context of varying environments and stressors. Thus, dysfunctional and surplus organelles are cleared from tissues through the process of autophagy (Okamoto, 2014). This clearance of organelles, or organellophagy, varies from the bulk degradation process of starvation-induced autophagy in that it involves the degradation of specific cellular components and is, thus, categorized as selective

Autophagy and Cell Death

Programmed cell death is an evolutionarily conserved process that occurs in multicellular organisms, enabling the removal of damaged and unwanted cells. Initially, the classification of different types of cell death was based largely on morphological criteria. However, the NCCD has proposed five different modes of programmed cell death, including extrinsic apoptosis, intrinsic apoptosis, regulated necrosis, mitotic catastrophe, and autophagic cell death (Galluzzi et al., 2012). These processes

Conclusions

Here, we have described the role of autophagy in both cell survival and cell death. Autophagy is most often thought of as a cell survival mechanism, ridding cells of damaged organelles, protein aggregates, or providing energy during periods of stress such as starvation. However, mounting evidence points to the role of autophagy in programmed cell death in varying tissues and organisms.

Cellular homeostasis is crucial for the survival of a cell and is dependent on the maintenance of organelle

Acknowledgments

The authors gratefully acknowledge G. Kabachinski and P. Velentzas for critically reading the manuscript. Research on this subject is supported by the National Institutes of Health (GM079431, GM111658, CA159314, AI099708) to E.H.B. and A.L.A. was supported by T32 CA 130807-06 A1. E.H.B. is an Ellison Medical Foundation Scholar.

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