The good, the bad and the autophagosome: exploring unanswered questions of autophagy-dependent cell death

Abstract

The recent discovery of autosis as a variant of autophagy-dependent cell death has challenged the conventional understanding of cell death and programmed cell death in cellular decision making. In contrast to previous accounts of distinct cell death modalities, autosis occurs with high autophagic activity, in the absence of apoptotic and necrotic markers and yet is not fully regulated by typical autophagy markers. Given the metabolic importance of autophagic responses and the extensive cross-talk with both apoptosis and necrosis signalling, the classical and morphotype-driven characterization of cell death as pre-determined subroutines is being increasingly called into question. Furthermore, the conflicting evidence with regards to cell death induction through autophagy modulation in various cancer models highlights the lack of consensus over the extent to which autophagy assists in cell death ontrol and whether it is capable of being a bona fide lethal process. This review evaluates the evidence and context of autophagy-dependent cell death and delineates the role of an autophagic flux threshold associated with 'lethal' and 'non-lethal' autophagy and its role in autosis control. In doing so, cancer treatment avenues will be explored with regards to precision modulation of tumour autophagic flux to ascertain whether autosis induction may present a novel therapeutic strategy.

Ethoxysanguinarine, a Novel Direct Activator of AMP-Activated Protein Kinase, Induces Autophagy and Exhibits Therapeutic Potential in Breast Cancer Cells

“…However, the role of autophagy in cancer treatment is still controversial. On the one hand, autophagy may promote cell death (Denton and Kumar, 2018;Kriel and Loos, 2019); on the other hand, autophagy may play a supporting role in the malignant progression and drug resistance of tumors (Li et al, 2017;Mowers et al, 2017). In this study, we demonstrated that Eth can induce autophagosome biosynthesis, manifested by increased autophagosome formation, LC3-II conversion, and LC3B-puncta (Figures 2A-C).…”

Autophagy and Cathepsin D mediated apoptosis contributing to ovarian follicular atresia in the Nile tilapia

“…The low vascularization of the theca during most of the follicular regression (Miranda et al, ) may justify the induction of autophagy to maintain cell homeostasis through clearance and selective removal of protein aggregates and dysfunctional organelles (Ryter, Cloonan, & Choi, ; Sever & Demir, ). However, under prolonged metabolic stress, autophagy may contribute to the provision of energy for apoptotic execution (Chiarelli, Agnello, Bosco, & Roccheri, ; Kriel & Loos, ). In support of this hypothesis, we observed follicular cells with highly electron‐lucid cytoplasm and a shortage of organelles under the electron microscope.…”

Autophagy and cardiac aging

“…Autophagy is a lysosomal degradation process. This selfdigestion process was initially considered as a cell death mechanism (type II programmed cell death) and indeed excessive autophagy triggers a specific form of cell death, termed autosis (reviewed by Kriel and Loos in this issue [21]). The molecular and functional interaction between autophagy and apoptosis has been demonstrated, as reviewed by Denton and Kumar in this issue [22].…”