Trends in Biochemical Sciences
ReviewCell death by necrosis: towards a molecular definition
Introduction
The death of a cell can be defined as an irreversible loss of plasma membrane integrity [1]. Historically, three types of cell death have been distinguished in mammalian cells by morphological criteria. Type I cell death, better known as apoptosis, is defined by characteristic changes in the nuclear morphology, including chromatin condensation (pyknosis) and fragmentation (karyorrhexis); minor changes in cytoplasmic organelles; and overall cell shrinkage, blebbing of the plasma membrane and formation of apoptotic bodies that contain nuclear or cytoplasmic material. All of these changes occur before plasma membrane integrity is lost. Type II cell death is characterized by a massive accumulation of two-membrane autophagic vacuoles in the cytoplasm. Type III cell death, better known as necrosis, is often defined in a negative manner as death lacking the characteristics of the type I and type II processes. A classical positive definition of necrosis based on morphological criteria (early plasma membrane rupture and dilatation of cytoplasmic organelles, in particular mitochondria) 1, 2, can now be updated and refined.
The distinction between cell death types is important, particularly because necrosis is often associated with unwarranted cell loss in human pathologies 3, 4, 5 and can lead to local inflammation, presumably through the liberation of factors from dead cells that alert the innate immune system 2, 3, 6. In addition, it seems that clearance of apoptotic cells operates differently from that of necrotic cells [7]. Whereas apoptotic cells (which shrink) are engulfed completely by phagocytes, necrotic cells (which swell) are internalized by a macropinocytotic mechanism, meaning that only parts of the cell are taken up by phagocytes [8].
Our intention here is to discuss recent results that might facilitate a shift from the negative definition of necrosis (which phenomenologically is neither apoptosis nor autophagy, and biochemically requires neither caspases nor autophagy) to a more positive definition of this particular modality of cell death. In short, could necrotic cell death be programmed in the sense that it would constitute a stereotyped, evolutionarily designed, sequence of biochemical events?
Section snippets
Approaching a programmed course of necrotic cell death
For the purpose of our discussion, we consider a few well-characterized experimental systems in which elements of the necrotic pathway have been described and can be condensed into a cumulative rather than consensual sequence of events. The six experimental systems considered (Table 1) are heterogeneous in terms of cell types and species (several mammalian cell types, the nematode Caenorhabditis elegans and the slime mold Dictyostelium discoideum) and death inducers (from ischemia to ligands of
Programmed occurrence of necrotic cell death?
Obviously, in harsh conditions such as detergent stress or freeze-thawing, cells die through a non-regulated, poorly defined, necrotic process. However, at variance with the classical textbook notion that it is merely an accidental consequence of non-physiological stress, necrosis might be programmed in terms of both its course and its occurrence. The cascade of events shown in Figure 1 suggests that there is a programmed ‘course’ of events (i.e. how necrosis manifests) within the necrotic
Programmed necrotic cell death as a default pathway
The idea that necrosis constitutes a (or even the) default cell death pathway is supported by the observation that inhibition of essential apoptotic events plus inhibition of autophagy can induce necrosis in, for example, immortalized baby mouse kidney epithelial (iBMK) cells that undergo cell death in response to hypoxia in vitro and in vivo [19]. In this model, suppression of mitochondrial membrane permeabilization (MMP) by the simultaneous knockout of the pro-apoptotic proteins Bax and Bak,
Towards necrosis-specific molecular processes?
Mutagenesis studies have identified genes that are required for apoptotic cell death, such as ced3, ced4 and ced9 in C. elegans and their homologs in other species [27]. An unambiguous definition of necrotic cell death would considerably benefit from the identification of molecules or processes that are specifically required for necrosis. Such a discovery would also further upgrade necrotic cell death from a programmed pathway to a specific function. Some candidate molecules have been recently
Therapeutic manipulation of necrosis
Necrosis induced by non-specific stimuli, such as ischemia, trauma or infection, often involves receptor-mediated cell death, for example, as a consequence of either TNFα production or excitotoxicity. As a result, blockade of surface receptors or interruption of the signals that emanate from such receptors might be a prime choice for the therapeutic inhibition of necrosis. As discussed earlier, several enzymes have a rate-limiting role in receptor- or damage-induced necrosis, suggesting that
Concluding remarks
As we have discussed, accumulating evidence supports a ‘sequence’ of events that characterize necrotic cell death at both the phenomenological and the biochemical level, thereby reflecting a programmed course of events in the dying necrotic cell and contributing to a definition of necrotic cell death. In addition, in some circumstances the ‘occurrence’ of necrotic cell death is programmed. Does this mean that necrotic cell death can be considered a bona fide programmed type of cell death in
Acknowledgements
P.G. is supported by the EU (Trans-death), INSERM, CNRS and ARC. G.K. is supported by a special grant from Ligue Nationale contre le Cancer, EU (Trans-Death, Death Train) and INSERM.
Glossary
- AIF
- apoptosis-inducing factor, a flavoprotein normally located in the mitochondrial intermembrane space that can translocate to the nucleus on induction of cell death. Mitochondrial AIF participates in local redox homeostasis, whereas nuclear AIF can contribute to chromatin condensation and degradation.
- Akt
- a survival kinase (also called protein kinase B or PKB) that, when activated, indirectly enhances glucose metabolism and suppresses autophagy through the mTOR kinase.
- Atg
- a family of
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