There should always be a homeostatic balance between cell formation and cell death, and this balance is sustained by apoptosis to prevent cancer. Apoptosis is a physiological mechanism done by the cell to induce its own death. In fact, the mechanism is ATP-dependent and specific proteins mediate it. Besides, it doesn't cause tissue inflammation, and it’s triggered by cytoskeleton and DNA breakdown by proteases and endonucleases respectively.
Anatomical pathology of apoptosis:
Caspases cause the disruption of the cytoskeleton, this results in the loss of neighboring cells contact as the cell shrinks. Besides, the cell becomes highly eosinophilic, but the nucleus is highly basophilic during the process. Next, pyknosis occurs leaving the chromatin condensed as stain masses. Also, the dissolution of the nuclear envelope allows endonuclease to slice DNA into short segments, a process called karyorrhexis. Furthermore, both the cytoplasm and nucleus break into apoptotic masses leaving the cell by budding. Finally, macrophages come into action in a process called efferocytosis where they eliminate the apoptotic masses; thus, macrophages clears the apoptotic cells without any inflammation involving the nearby tissues.
Apoptosis intrinsic pathway:
The stimulation of the intrinsic pathway depends on intracellular stress that could be the result of many factors. In fact, these factors are UV-light or x-ray damaging DNA, hypoxia, chemotherapeutic agents, or simply misfolded proteins accumulation inside the cell which is the case in many diseases such as Parkinson or Huntington disease. Indeed, the intrinsic pathway is also called the mitochondrial pathway since the cellular stress causes cytochrome C to leave the mitochondria into the cytosol which stimulates caspases.
Intrinsic pathway regulators:
Both Bcl-2 family of genes and TP53 suppressor gene are responsible for the regulation of the intrinsic pathway. The first is an anti-apoptotic gene that produce bcl-2 protein, and the protein binds to APAF-1 inhibiting cytochrome C release from the mitochondria thus ending apoptosis. The second encodes the TP53 protein, and this protein role is to arrest cell cycle and suppress tumors. In other words, normally if the DNA is damaged, TP53 arrests the cell cycle at G1 phase. However, if the damage is severe and beyond fixation, TP53 activates BAX apoptosis genes which counters Bcl-2 anti-apoptosis genes.
A cell extrinsic pathway is activated when other cell(s) send death signals. Since the extrinsic pathway is receptor mediated, ligands produced by the signaling cells bind to the cell surface receptor resulting in apoptosis of the cell. This binding is done by 2 cytokines and it results in caspase. The first is TNF-alpha which is produced by macrophages, it binds to TNFR1 receptor found on cell surface. The second is Fas (CD95) receptor belonging to the TNF family, and it binds to Fas ligand (FasL).
Abnormal apoptosis complications:
-Tumorigenesis: where apoptosis rate decrease leads to the formation or development of tumors.
- autoimmune diseases: when immune cells acts against their own (self-reactive), they must be eliminated by apoptosis. Therefore, a decrease in apoptosis level leads to rheumatoid arthritis, systemic lupus erythematous (SLE), autoimmune lymphoproliferative syndrome and other autoimmune diseases.
-neurodegenerative diseases: when acute neurologic diseases involves both necrosis and apoptosis, apoptosis also plays a role in chronic neurodegenerative disorders such as Parkinson’s disease, Huntington disease and Alzheimer disease.
-myocardial infarction: during the reperfusion phase apoptosis occurs leading to more myocardial damage.
-Zlender V. Apoptoza--programirana smrt stanice [Apoptosis--programmed cell death]. Arh Hig Rada Toksikol. 2003 Dec;54(4):267-74. Croatian. PMID: 14994649.
-Akhtar F, Bokhari SRA. Apoptosis. [Updated 2021 May 16]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2022 Jan-.