Several paradigms of caspase-independent cell death have been characterized in diverse species. Most can be grouped into three main types, mitotic catastrophe, autophagy, and necrosis. Proteins that normally serve physiological functions can be released from mitochondria after MOMP and once in the cytosol they act as death executors. The functions of some such proteins have been investigated in mammalian cells as well as in C. elegans and Drosophila. These studies point towards conserved mechanisms of caspase-independent cell death. Interestingly, while some of these effectors trigger caspase-independent cell death in mammals, they preferentially engage caspase-dependent apoptotic cell death in invertebrates.
This indicates that caspase-independent cell death mechanisms may represent more recent additions to the cell death program.
Studies in yeast and in mammalian cells indicate that autophagy is a mediator of both cell survival and cell death. Starvation causes formation of autophagosomes, partial degradation of cell contents and recycling of the degraded components, which provides the cell with the energy required to overcome the shortage of nutrients. Nevertheless, abnormally high levels of autophagy may promote cellular destruction instead. Furthermore, the process of autophagy is intimately linked with both apoptosis and necrotic cell death. Necrosis was traditionally considered as merely the chaotic breakdown of cells. However, several recent studies in C. ele-gans indicate that specific molecular mechanisms are involved in the necrotic destruction of the cell. Because necrosis is implicated in many devastating human disorders, such as neurodegenerative diseases and stroke, elucidation of the biochemical events that transpire during necrosis has the potential to provide targets for effective pharmacological interventions.
In addition to the three major categories of caspase-independent cell death, novel cell death paradigms that do not involve caspase function are emerging. Genetic and molecular dissection of these examples of cell death in invertebrate models may reveal new mediators of cell death with relevance to human pathological conditions.
Acknowledgments We gratefully acknowledge the contributions of numerous investigators, whom we did not include in this review. Work in the authors' laboratory is funded by grants from EMBO and the EU 6th Framework Programme to N.T.
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