Apoptosis and autophagy: regulatory connections between two supposedly different processes

Abstract

Apoptosis and autophagy are genetically-regulated, evolutionarily-conserved processes that regulate cell fate. Both apoptosis and autophagy are important in development and normal physiology and in a wide range of diseases. Recent studies show that despite the marked differences between these two processes, their regulation is intimately connected and the same regulators can sometimes control both apoptosis and autophagy. In this review, I discuss some of these findings, which provide possible molecular mechanisms for crosstalk between apoptosis and autophagy and suggest that it may be useful to think of these processes as different facets of the same cell death continuum rather than completely separate processes. KeywordsAutophagy; Apoptosis; Bcl-2, FADD; Atg 5In the early to mid 1990s there was a rapid increase in our understating about the regulation of apoptosis. Fifteen or so years later we are in the midst of a similarly exciting period for understanding autophagy with very rapid growth of publications on the regulation and function of this process (1). Autophagy (the form of autophagy discussed here is macroautophagy, other forms-microautophagy and chaperone-mediated autophagy share the same lysosomal degradation mechanism but differ in the way that material is delivered to the lysosome) is a degradative process involving sequestration of parts of the cytoplasm in double membrane vesicles (autophagic vesicles or autophagosomes) that fuse with lysosomes forming the autophagolysosome. In the autophagolysosome, the cytoplasmic material that was engulfed is hydrolyzed and the resulting amino acids and other macromolecular precursors can be recycled (2-4), see Fig 1 for a schematic of the process. Autophagy is a mechanism by which organelles are removed and is the primary degradation mechanism for long-lived proteins and thus maintains quality control for proteins and organelles. Autophagy is ubiquitous in eukaryotic cells and important in development and in diverse pathophysiological conditions (5)-for example providing protection against neurodegeneration (6,7), infections (8,9) and tumor development (10-13). Cells that are deficient in autophagy also demonstrate enhanced chromosomal instability (14,15), which may be related to the tumorigenesis associated with autophagy deficiency.Autophagy is important in cell death decisions and can protect cells by preventing them from undergoing apoptosis. For example, increased autophagy in nutrient deprived or growth factorwithdrawn cells allows cell survival (16,17) by inhibiting apoptosis. Autophagy also protects cells from various other apoptotic stimuli (18). It is not clear how autophagy stops cells from undergoing apoptosis; one suggested mechanism is the sequestration of damaged mitochondria (18) thus preventing released cytochrome c from being able to form a functional apoptosome NIH Public Access Autophagic cell death (also known as Type II programmed cell death to distinguish it from apoptosis or Type I programmed cell death) (20-22) has been describ...

Autophagy, Apoptosis, Mitoptosis and Necrosis: Interdependence Between Those Pathways and Effects on Cancer

“…The autophagy response involving FADD is much more pronounced when apoptosis is blocked, i.e., by caspase inhibition. This suggests that autophagy and apoptosis are induced simultaneously by the FADD death domain, at least in normal epithelial cells (Thorburn 2008), but since apoptotic cell death progresses faster, this is a dominantly observed form of cell death. The full onset of autophagy (or necrosis) emerges only when caspase inhibitors are applied.…”

Histologic changes of the fetal membranes after fetoscopic laser surgery for twin-twin transfusion syndrome

“…One study has shown that when placed in culture, amnion epithelial cells are capable of endocytosis and autophagy (selfeating) to adapt to the abrupt changes in the environment (19). For many cell types, the process of autophagy has been well-studied in relation to cellular adaptation to stress and as means to delay apoptosis in low nutrient conditions (20,21 Articles Papanna et alturn to autophagy or apoptosis in response to changes in AF concentration occurring in vivo such as in instances of polyhydramnios (e.g., the recipient sac of pregnancies with TTTS) or postamnioinfusion during FLS procedures. The objectives of this study were: (i) to explore systematically the array of histological changes of the fetal membranes occurring post-FLS for TTTS both at the trocar insertion site and at distance; (ii) to explore whether over-dilution of AF on the recipient side which is a common phenomenon in TTTS pregnancies could be mechanistically linked to histologic changes in the amniochorion and to the high incidence of PPROM post-FLS.…”

“…One study has shown that when placed in culture, amnion epithelial cells are capable of endocytosis and autophagy (selfeating) to adapt to the abrupt changes in the environment (19). For many cell types, the process of autophagy has been well-studied in relation to cellular adaptation to stress and as means to delay apoptosis in low nutrient conditions (20,21 Articles Papanna et al…”

Cisplatin-induced macroautophagy occurs prior to apoptosis in proximal tubules in vivo

“…The discovery of autophagy-related proteins in yeast has revealed the existence of an evolutionarily conserved mechanism for the formation of autophagosomes that sequester cytoplasmic material before they fuse with the endo/lysosomal compartment [3,4]. Light chain 3-II (LC3-II) is specifically located on double membrane-bound autophagosomes that envelop disused proteins or organelles.…”