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Review
. 2012 Jan;19(1):87-95.
doi: 10.1038/cdd.2011.146. Epub 2011 Nov 4.

Cell death by autophagy: facts and apparent artefacts

D Denton  1 , S Nicolson, S Kumar
Affiliations
Review

Cell death by autophagy: facts and apparent artefacts

D Denton et al. Cell Death Differ. 2012 Jan.

Abstract

Autophagy (the process of self-digestion by a cell through the action of enzymes originating within the lysosome of the same cell) is a catabolic process that is generally used by the cell as a mechanism for quality control and survival under nutrient stress conditions. As autophagy is often induced under conditions of stress that could also lead to cell death, there has been a propagation of the idea that autophagy can act as a cell death mechanism. Although there is growing evidence of cell death by autophagy, this type of cell death, often called autophagic cell death, remains poorly defined and somewhat controversial. Merely the presence of autophagic markers in a cell undergoing death does not necessarily equate to autophagic cell death. Nevertheless, studies involving genetic manipulation of autophagy in physiological settings provide evidence for a direct role of autophagy in specific scenarios. This article endeavours to summarise these physiological studies where autophagy has a clear role in mediating the death process and discusses the potential significance of cell death by autophagy.

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Figures

Figure 1
Figure 1
Various steps involved in macroautophagy. Autophagy is the process of engulfment of cytoplasmic material, including organelles and protein aggregates, into a double membrane vesicle, the autophagsosome. Induction of autophagy is initiated by activation of the Atg1 complex (Atg1/Atg13/Atg17 and other components). Autophagosome nucleation requires class-III phosphatidylinositol-3-kinase (Vps34) and Beclin-1/Atg6 to recruit proteins and lipids required for autophagosome formation. Elongation and completion are mediated by two-ubiquitin-like systems, which result in lipidated LC3 binding to the autophagosome membrane. The completed autophagosome then fuses with the lysosome, where the autophagosome contents are degraded
Figure 2
Figure 2
Autophagy in cell survival and cell death. In most circumstances autophagy acts as a survival mechanism, for example, by lowering cell metabolism and supplying nutrients under starvation conditions, or by maintaining quality control in rapidly growing cells (such as oncogene-transformed cells). Autophagy also has specific and context-dependent roles in cell death. It can promote both caspase-dependent apoptotic cell death (e.g., during Drosophila larval salivary gland degradation) and non-apoptotic cell death when caspases are inhibited (e.g., in certain tumour cells). In addition, autophagy has a more direct role in mediating cell death in specific contexts (e.g., in the degradation of Drosophila larval midgut). The exact mechanism(s) regulating autophagic cell death remains to be determined
Figure 3
Figure 3
Blocking autophagy delays removal of the Drosophila larval midgut. An example where autophagy seems to have a direct role in PCD is the removal of the Drosophila larval midguts during larval–pupal transition. Morphology of dying midguts at 4 h relative to puparium formation (RPF) (left) and histological analysis of paraffin sections at 12 h RPF. A significant delay in midgut histolysis when autophagy is inhibited by knocking down the Atg1 gene (Atg1 IR) as seen by the presence of less contracted gastric caeca (left) and a less condensed midgut (right) compared with a control, as indicated by arrows. Inhibition of caspases by expression of baculovirus p35 has no effect on midgut degradation. Combined knockdown of Atg1 and p35 expression shows a delay in midgut histolysis, as seen by the presence of gastric caeca (arrows) that is similar to Atg1 knockdown alone
Figure 4
Figure 4
Autophagy induction in response to activated Ras can result in cell growth and survival or cell death. Expression of activated Ras can induce autophagy and this has different consequences depending on the context. Acute overexpression of activated Ras induces Noxa and Beclin-1, which results in Mcl-1 dissociation from Beclin-1 and induction of caspase-independent autophagic cell death. Sustained overexpression of Ras leads to metabolic stress. In this scenario autophagy promotes cell survival and growth by overcoming cellular energy deficit and/or maintaining organelle quality control in rapidly dividing transformed cells
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