Autophagy-dependent cell death – where, how and why a cell eats itself to death

Abstract

Autophagy as a means of cell killing was first advanced by Clark's phenotypic description of 'Type II autophagic cell death' in 1990. However, this phenomenon later came into question, because the presence of autophagosomes in dying cells does not necessarily signify that autophagy is the cause of demise, but rather may reflect the efforts of the cell to prevent it. Resolution of this issue comes from a more careful definition of autophagy-dependent cell death (ADCD) as a regulated cell death that is shown experimentally to require different components of the autophagy machinery without involvement of alternative cell death pathways. Following these strict criteria, ADCD has been validated in both lower model organisms and mammalian cells, highlighting its importance for developmental and pathophysiological cell death. Recently, researchers have defined additional morphological criteria that characterize ADCD and begun to explore how the established, well-studied autophagy pathway is subverted from a survival to a death function. This Review explores validated models of ADCD and focuses on the current understanding of the mechanisms by which autophagy can kill a cell.

<p>Genipin Induces Autophagy and Suppresses Cell Growth of Oral Squamous Cell Carcinoma via PI3K/AKT/MTOR Pathway</p>

“…30 Autophagy acts a key role in cell survival, which is a key pathway for homeostasis, development, and other pathophysiological processes. 31 Moreover, autophagy showed an increase in the expression of autophagy-related proteins such as LC3-II, Beclin-1, and ATG5, with a decrease in the expression of p62. 32 Kinarivala et al 33 reported that the activated Beclin-1 could induce autophagy.…”

Non-Apoptotic Cell Death Signaling Pathways in Melanoma

“…This stage of autophagy can be inhibited by chloroquine, hydroxychloroquine and bafilomycin A1 that disturb acidification of the lysosomes ( Figure 2) [55]. The role of autophagy still remains elusive as it can be either a cytoprotective response or followed by induction of different modalities of cell death [60][61][62]. According to the most current recommendations of nomenclature, the term "autophagy-dependent cell death" can be used exclusively when observed cell death is strictly reliant on the autophagic machinery [5,63].…”

Phosphoinositides: multipurpose cellular lipids with emerging roles in cell death

“…post-ischaemic injury, starvation) or chemical (e.g. vintexin treatment) conditions, autophagy can result in autophagic cell death (ACD) [67][68][69]. Typical characteristics of ACD include membrane rupture, numerous autophagolysosomes, and enlargement of major cellular organelles [70][71][72].…”

“…Typical characteristics of ACD include membrane rupture, numerous autophagolysosomes, and enlargement of major cellular organelles [70][71][72]. Mechanistically, ACD is the lethal outcome of disturbed autophagic homoeostasis via excessive self-consumption of cellular content, uncontrolled mitophagy and autosis (Na + /K + -ATP-dependent ACD) [68,69].…”

“…A shift from basal autophagy to ACD has been linked with hyperactivation of Vps34-Beclin-1, overexpression of Beclin-1, downregulation of the molecular brakes of Beclin-1, hyperactivation of non-canonical autophagic pathways and certain death-specific factors (e.g. apolipoprotein 1 ApoL-1) [67,68,85]. ApoL-1, a BH3-only lipid-binding protein, can induce ACD, speculatively via disruption of phosphatidic acid-mTOR interaction and inhibition mitochondrial cardiolipin-associated apoptosis [85].…”