Overview: Apoptosis

Apoptosis, also known as programmed cell death (PCD), is a genetically programmed event in animal cells. It's occurrence is vital to major developmental and regulatory events such as embryogenesis and tissue homeostasis.

Simplified Mechanism: Apoptosis

Fig 1: The Mechanism of Apoptosis Simplified

Apoptosis can be initiated by two main mechanisms, the intrinsic pathway and the extrinsic pathway.

Inititation of either pathway results in the same regulatory and effector mechanisms.

Initiation leads to the expression of regulatory apoptotic genes that give rise to the initiator and effector caspases.

Once an initiator caspase is cleaved, the caspase cascade is activated. This cascade causes the cleavage of effector caspases, which ultimately lead to the key cellular events that characterise an apoptosing cell.

This article is only an overview of the regulation of apoptosis, for further information on the specifics involved in the control and regulation of cell death read our article on that here.

Apoptosis: The Intrinsic and Extrinsic Pathways

Intrinsic:

  • The intrinsic pathway of apoptosis is activated upon cellular stresses such as decreased oxygen, increased reactive oxygen species and DNA damage.
  • Stressors cause initiator caspases within the mitochondria and endoplasmic reticulum to be cleaved. This then activates downstream effector caspases, ultimately leading to cell death.
  • The intrinsic pathway is governed by the Bcl-2 family of proteins. These proteins are either pro-apoptotic or anti-apoptotic.
  • Apoptotic Bcl-2 proteins, such as Bad, interact and activate the release of cytochrome C from the mitochrondria which eventually inititates the caspase cascade.
  • Effector caspases are activated and these eventually cause cell death.

 

Extrinsic:

  • The extrinsic pathway of apoptosis is activated upon the binding of a death ligand to a death receptor on the cell membrane.
  • Death receptors are FAS and TNF receptors and activated by FAS or TNF ligands.
  • Activation of these receptors causes the cleavage of initiator caspases within the cytoplasm.
  • This then activates downstream effector caspases, ultimately leading to cell death.

 

 

Overview: Key Cellular Events in Apoptosis

Once apoptosis is initiated, there are key cellular events which arise. These are:

  1. Shrinking and rounding of the cell membrane (Fig 2a)
  2. DNA compaction via chromatin condensation (Fig 2b)
  3. DNA fragmentation (Fig 2c)
  4. Cytoplasm gets denser and organelles become compacted (Fig 2c)
  5. Membrane blebbing which leads to vesicle formation (Fig 2c)
  6. The cell is packaged into these vesicles, which are termed apoptotic bodies (2d)
  7. Phagocytosis of the apoptotic bodies occurs

Simplified: The Key Cellular Events of Apoptosis

Fig 2: Key Cellular Events in Apoptosis

Why Is Apoptosis Important?

Apoptosis is important in every day of our lives, as many processes rely on apoptosis to occur. Furthermore, research has shown that the inhibition or hyperactivity of apoptosis can cause disease. Below is a short overview of the importance of apoptosis:

  • Apoptosis is vital for the formation of digits, organs and limbs in embryogenesis
  • Apoptosis is needed in the strict process of tissue homeostasis in the developed animal
  • Increased apoptosis causes the vascular calcification seen in end-stage kidney failure, sadly little can be done for this and many patients die from the effects of arterial calcification
  • Increased apoptosis can lead to larger plaque formation in coronary heart disease
  • Decreased apoptosis is seen in many aggressive cancers, chemotherapy targets cancer cells and induces them to die
  • In arthrtitis, the increased levels of inflammation cause continual activation of cell death leading to the degradation and damage of affected joints

References

  • Alberts, B., Johnson, A., Lewis, J., Raff, M., Roberts, K.,Walter, P (2002). Molecular Biology of the Cell. 4th ed. New York: Garland Science 
  • Gutter, M.G. (2000). Caspases: key players in programmed cell death. Current Opinion in Structural Biology. 10, 649-655 
  • Renehan, A.G., Booth, C., Potten, C.S. (2001). What is apoptosis, and why is it important? British Medical Journal. 322, 1536-1538 
  • Zimmermann, K.C., Bonzon, C., Green, D.R. (2001). The machinery of programmed cell death. Pharmacology & Therapeutics. 92, 57-70 

       

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