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Mechanisms of cell death
D J Fawthrop1, A R Boobis, D S Davies
1Department of Clinical Pharmacology, Royal Postgraduate Medical School, Hammersmith Hospital, London, UK.
Abstract:
Two distinct morphological patterns of cell death have been recognized, termed necrosis and apoptosis. Apoptosis, or programmed cell death, occurs in both physiological and pathological conditions. It arises due to an elevation of cytosolic free calcium concentration resulting in activation of a nuclear endonuclease. Activated endonuclease produces oligonucleosome-length DNA fragments. This DNA cleavage can directly precipitate cell death. Both glucocorticoids and TCDD may induce apoptosis by production of a heat labile factor that mediates calcium influx whereas tributyltin causes the opening of calcium channels. Evidence that perturbation in calcium homeostasis is an important event in cell necrosis is becoming increasingly persuasive, but the events that propagate the lesion are still unclear. Despite evidence for cytoskeletal disruption, activation of degradative enzymes such as proteases and phospholipase A2 and stimulation of other enzymes such as poly (ADP-ribose) polymerase, the exact role that these play in cell killing is not resolved. Indeed, recently the radical dichotomy between apoptosis and necrotic cell death has come into question. It is clear that further work is required to determine the role played by some elements of the apoptotic process in chemically induced cell death.
Insights
This study explores cell death mechanisms, focusing on apoptosis and necrosis. It highlights calcium
Area of Science:
- Biochemistry
- Cell Biology
- Toxicology
Background:
- Two primary cell death patterns exist: necrosis and apoptosis (programmed cell death).
- Apoptosis involves nuclear endonuclease activation, leading to DNA fragmentation.
- Calcium homeostasis disruption is implicated in both cell death types.
Purpose of the Study:
- To investigate the role of calcium in apoptosis and necrosis.
- To clarify the mechanisms underlying chemically induced cell death.
- To examine the relationship between apoptosis and necrosis.
Main Methods:
- Review of existing literature on cell death pathways.
- Analysis of factors inducing apoptosis, such as glucocorticoids, TCDD, and tributyltin.
- Examination of cellular events in necrosis, including cytoskeletal disruption and enzyme activation.
Main Results:
- Apoptosis can be induced by factors mediating calcium influx or channel opening.
- Calcium perturbation is increasingly recognized in necrosis, though propagation mechanisms remain unclear.
- The distinct separation between apoptosis and necrosis is being questioned.
Conclusions:
- Calcium homeostasis plays a critical role in both apoptosis and necrosis.
- Further research is needed to fully elucidate the mechanisms of chemically induced cell death.
- The interplay between apoptotic and necrotic pathways requires further investigation.