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Apoptotic and necrotic cell death induced by death domain receptors
G Denecker1, D Vercammen, W Declercq
1Department of Molecular Biology, Flanders Interuniversity Institute for Biotechnology and University of Ghent, Belgium.
Abstract:
Apoptosis and necrosis are two distinct forms of cell death. Caspases are indispensable as initiators and effectors of apoptotic cell death and are involved in many of the morphological and biochemical features of apoptosis. Major changes in mitochondrial membrane integrity and release of proapoptotic factors, such as cytochrome c from the mitochondrial intermembrane space, play an important sensor and amplifying role during apoptotic cell death. In vitro studies of cell death in cell lines have revealed that inhibition of the classical caspase-dependent apoptotic pathway leads in several cases to necrotic cell death. Thus, the same cell death stimulus can result either in apoptotic or necrotic cell death, depending on the availability of activated caspase. Therefore, death domain receptors may initiate an active caspase-independent necrotic signaling pathway. In this review, we describe what is known about the apoptotic and necrotic cell death pathways. Principal elements of necrosis include mitochondrial oxidative phosphorylation, reactive oxygen production, and non-caspase proteolytic cascades depending on serine proteases, calpains, or cathepsins.
Insights
Apoptosis and necrosis are distinct cell death forms. Caspases mediate apoptosis, but their inhibition can trigger necrosis, highlighting the stimulus-dependent nature of cell death pathways.
Area of Science:
- Cell Biology
- Biochemistry
Background:
- Apoptosis and necrosis are distinct programmed cell death mechanisms.
- Caspases are key regulators of apoptosis, orchestrating its characteristic features.
- Mitochondrial integrity and cytochrome c release are critical in apoptotic signaling.
Purpose of the Study:
- To review and elucidate the distinct molecular pathways of apoptosis and necrosis.
- To explore the interplay between caspase-dependent and independent cell death routes.
- To highlight the factors influencing whether a cell undergoes apoptosis or necrosis.
Main Methods:
- Review of existing literature on apoptosis and necrosis.
- Analysis of molecular mechanisms, including caspase involvement and mitochondrial pathways.
- Comparison of signaling cascades initiated by death domain receptors.
Main Results:
- Caspase inhibition can redirect apoptotic stimuli towards necrotic cell death.
- Mitochondrial function, oxidative stress, and specific proteases are central to necrosis.
- Death domain receptors can activate caspase-independent necrotic pathways.
Conclusions:
- Cell death fate (apoptosis vs. necrosis) is stimulus and pathway-dependent.
- Caspase availability is a critical determinant in switching between apoptotic and necrotic cell death.
- Necrosis involves distinct molecular players, including mitochondrial activity and non-caspase proteases.