Apoptosis – Definition and Importance


Apoptosis Cell Disassembly
Steps of apoptosis (A. Smith, M. Parkes, et al., CC Attribution 4.0 International License)

Apoptosis comes from the Greek words “apo” (away from) and “ptosis” (falling), literally meaning the “falling off” of cells. It is a form of programmed cell death, where cells dismantle themselves in a controlled and regulated manner. This mechanism is crucial for maintaining cellular integrity and organismal homeostasis.

  • Apoptosis is programmed cell death.
  • It is an essential process in development, growth, repair, and immune function.
  • However, excessive or insufficient apoptosis results in serious health conditions.

The Purposes and Importance of Apoptosis

Apoptosis serves several vital purposes:

  1. Development and Morphogenesis: It shapes tissues and organs during embryonic development.
  2. Immune Function: It eliminates harmful or infected cells, contributing to immune system regulation.
  3. Homeostasis and Cell Proliferation Balance: By removing old, damaged, or unnecessary cells, apoptosis maintains healthy tissue balance. The average adult human loses between 50 and 70 billion cells daily through apoptosis.

History

German scientist and philosopher Carl Vogt first proposed the concept apoptosis in 1842. Anatomist Walther Flemming outlined the process of programmed cell death in 1885. In 1972, John Kerr, Andrew Wyllie, and Alastair Currie published a paper in the British Journal of Cancer concerning a form of natural controlled cell death that was distinct from necrosis. Their research shed light on a physiological process that was an integral part of an organism’s growth and development. Sydney Brenner, H. Robert Horvitz, and John Sulston received the 2002 Nobel Prize in Medicine for work identifying the genes controlling apoptosis.

Apoptosis vs Necrosis

Apoptosis vs Necrosis
Apoptosis is a necessary and planned cell death, while necrosis results from injury or trauma.

The key difference between apoptosis and necrosis lies in their characteristics and consequences:

  • Apoptosis is orderly and does not elicit an inflammatory response. It involves cell shrinkage, chromatin condensation, membrane blebbing, and the formation of apoptotic bodies which undergo phagocytosis. While a cell dies, the ones around it are unaffected.
  • Necrosis, in contrast, is a form of traumatic cell death resulting from external factors like toxins or injury, leading to cell swelling, rupture, and inflammation. The release of damaged cell contents affects surrounding cells and potentially the rest of the body.

Is Apoptosis Bad? Is It Good?

Apoptosis is neither inherently good nor bad; its impact depends on the context and balance within the body. It’s a critical process for normal functioning and health, but when its regulation is disrupted, it contributes to disease.

The Good:

  • Maintaining Cellular Balance: Apoptosis plays a crucial role in maintaining the right number of cells in the body, ensuring that cell proliferation and death are in balance.
  • Developmental Processes: During embryonic development, apoptosis shapes tissues and organs. For example, it’s vital for the proper formation of fingers and toes in humans.
  • Eliminating Damaged Cells: Apoptosis eliminates cells with DNA damage or those infected by viruses, preventing them from becoming cancerous or spreading infection.
  • Immune System Regulation: It helps remove immune cells after they have served their purpose, preventing autoimmune reactions.

The Bad:

  • Excessive Apoptosis: When apoptosis occurs too frequently, it causes diseases. For instance, excessive neuronal apoptosis is implicated in neurodegenerative diseases like Alzheimer’s and Parkinson’s.
  • Insufficient Apoptosis: Conversely, insufficient apoptosis leads to uncontrolled cell proliferation, as seen in cancer. Failure to remove damaged cells contributes to the development of tumors.
  • Chronic Diseases: There is an association between dysregulated apoptosis and various chronic conditions, such as rheumatoid arthritis and type 1 diabetes.

Apoptosis Pathways

Two main pathways trigger apoptosis:

  1. Intrinsic (Mitochondrial) Pathway: Initiated from within the cell, it involves mitochondrial release of cytochrome c, leading to caspase activation.
  2. Extrinsic (Death Receptor) Pathway: Triggered by external signals, this involves death receptors on the cell surface activating caspases.

Stages of Apoptosis

Apoptosis is a highly regulated and controlled process that unfolds in distinct stages, each characterized by specific cellular changes and biochemical events.

  1. Initiation: Internal or external signals trigger the apoptosis pathways.
  2. Early Apoptosis: Key indicators include cell shrinkage, chromatin condensation, and membrane blebbing.
  3. Execution Phase: Caspases, the main executioners, dismantle the cell components.
  4. Phagocytosis: Apoptotic bodies are engulfed and digested by phagocytes, ensuring a clean and inflammation-free process.

1. Initiation Phase

The initiation phase marks the beginning of apoptosis, where the cell receives a signal to start the apoptotic process. These signals are either internal (like DNA damage or stress signals) or external (such as binding of death ligands to cell receptors).

2. Early Apoptosis: Induction of Changes

This stage features observable early signs of apoptosis:

  • Cell Shrinkage: The cell begins shrinking and reducing in volume. This change is one of the earliest morphological indications of apoptosis.
  • Chromatin Condensation: Chromatin, the complex of DNA and proteins in the nucleus, becomes densely packed and segmented. This is known as pyknosis.
  • Membrane Blebbing: The cell membrane starts to form bubble-like protrusions known as blebs. Blebbing occurs due to the breakdown of the cytoskeleton, a network of protein filaments that maintain cell shape.
  • Phosphatidylserine Externalization: Normally located on the inner leaflet of the cell membrane, phosphatidylserine is flipped to the outer leaflet, signaling phagocytic cells to engulf the dying cell.

3. Execution Phase: Dismantling the Cell

  • Caspase Activation: Caspases, a family of protease enzymes, are the main executioners in apoptosis. They activate in a cascade and are responsible for degrading vital cellular components.
  • Breakdown of Cellular Components: Caspases cleave various cellular proteins, causing the breakdown of the cytoskeleton, nuclear envelope, and other cellular structures.
  • DNA Fragmentation: Enzymes known as endonucleases cut DNA into small fragments, a process often referred to as DNA laddering due to its appearance in gel electrophoresis.

4. Phagocytosis of Apoptotic Bodies

  • Formation of Apoptotic Bodies: The cell breaks apart into smaller, membrane-bound vesicles called apoptotic bodies containing cellular contents and organelles.
  • Engulfment by Phagocytes: Phagocytic cells like macrophages recognize and engulf apoptotic bodies. This process recycles cell components without releasing harmful substances, preventing inflammation.

Impact of Excessive and Insufficient Apoptosis

There is a fine line between controlled cell death and the negative effects from losing too many cells or allowing an overgrowth:

  • Excessive Apoptosis: Leads to tissue atrophy and diseases like neurodegenerative disorders (Alzheimer’s, Parkinson’s), immune diseases, and heart failure.
  • Insufficient Apoptosis: Results in uncontrolled cell proliferation, contributing to cancer development and autoimmune diseases.

The Dual Role of Apoptosis in Cancer

Apoptosis plays a central role in both the development and treatment of cancer.

Apoptosis in Cancer Formation

Tumors result from insufficient apoptosis, while cancer also involves cells evading programmed death:

  • Cancer Initiation: One of the hallmarks of cancer is the evasion of apoptosis. In normal cells, faulty or mutated cells undergo apoptosis. When this mechanism fails, these aberrant cells survive and proliferate, leading to tumor formation.
  • Genetic Mutations: Many cancers involve mutations in genes that regulate apoptosis. For example, mutations in the p53 tumor suppressor gene, which plays a key role in inducing apoptosis in response to cellular stress, are common in various cancers.
  • Resistance to Cell Death: Cancer cells often develop resistance to apoptosis. This helps them to survive in adverse conditions that are common in tumors, like hypoxia or low nutrient availability.

Apoptosis in Cancer Treatment

At the same time, apoptosis is a powerful ally in cancer treatment:

  • Chemotherapy and Radiation: Many anticancer therapies work by inducing apoptosis in cancer cells. For example, chemotherapy and radiation cause DNA damage in cancer cells, triggering apoptosis. One challenge is selectively inducing apoptosis in cancer cells without affecting normal cells.
  • Targeted Therapies: These therapies involve drugs that specifically target pathways that regulate apoptosis in cancer cells. For example, drugs targeting the Bcl-2 family, which includes key regulators of the mitochondrial pathway of apoptosis, are effective against certain types of cancer.

References

  • Alberts, B.; Johnson, A.; et al. (2015). Molecular Biology of the Cell (6th ed.). Garland Science. ISBN 978-0815344322.
  • Indran, I.R.; Tufo, G.; et al. (2011). “Recent advances in apoptosis, mitochondria and drug resistance in cancer cells”. Biochimica et Biophysica Acta (BBA) – Bioenergetics. 1807 (6): 735–745. doi:10.1016/j.bbabio.2011.03.010
  • Krysko, D.V.; Vanden Berghe, T.; et al. (2008). “Chapter 16 Methods for Distinguishing Apoptotic from Necrotic Cells and Measuring Their Clearance”. Programmed Cell Death, General Principles for Studying Cell Death. Methods in Enzymology. 442: 307–41. ISBN 9780123743121. doi:10.1016/S0076-6879(08)01416-X
  • Smith, A.; Parkes, M.A.; et al. (2017). “Cell disassembly during apoptosis”. WikiJournal of Medicine. 4 (1). doi:10.15347/wjm/2017.008