Apoptosis – the process of programmed cell death
Apoptosis can be understood as an internally coordinated programmed cell death that has inevitable significance in a lot of physiologic and pathologic conditions. In Greek, apoptosis meant falling off or dropping off. The cell death is controlled and not accompanied by any tissue damage or inflammation.
In biological processes
As apoptosis is responsible for the mediation of cell death, it is observed under the following processes:
In physiological processes
- During the development of the embryo, to sculpt the tissues, organized cell destruction takes place.
- Involution of cells in tissues that are dependent on hormones. Eq, shedding of the endometrium
- Replacement proliferation preceded by normal cell destruction
In pathological processes
- Cell death in tumors
- Cell death in rejection reactions
- Cell death due to infections
- Heart diseases
- Pathological atrophy of organs
Importance of Apoptosis
Some of the important significances of apoptosis are:
- Apoptosis is very important for embryonic development as errors can lead to birth defects
- Cell death is often balanced with mitosis, thereby maintaining homeostasis
- Improper regulation of apoptosis contributes to human disease.
Characteristics of apoptosis
It is a process that occurs since the embryonic development stage of all living things. This process is an active cytological process that involves the consumption of energy. Both internal and external stimuli can trigger apoptosis.
The changes seen in the morphological features of an apoptotic cell are as follows:
- With increased cytoplasmic density, there occurs cell shrinkage
- Mitochondria are broken down and cytochrome C is released
- Chromatin gets condensed
- Cytoplasmic blebs and apoptotic bodies are formed
- Apoptotic cells are phagocytosed by adjacent healthy cells
Stages of Apoptosis
Even though a lot of physiological and pathological processes activate apoptosis in very different ways, the following events sum up the sequences.
- Initiation of apoptosis
- Activation of caspases
- Activation of death receptors
- Activation of growth controlling genes
There are two important pathways in which apoptosis takes place. They are the extrinsic pathway and intrinsic pathway.
The extrinsic pathway is also known as the death receptor pathway. The initiation of this pathway begins outside of the cell by the activation of pro-apoptotic receptors on the cell surface. This ligand binding causes the receptor to cluster and form a death-inducing signaling complex, also known as DISC. When DISC is activated, it has been observed that the extrinsic pathway adopts the same effector caspase mechanism as the intrinsic pathway.
Death receptors (DRs)
They are cell surface receptors. Apoptotic signals are initiated by specific ligands and are transmitted by death receptors. Caspases are activated by them within seconds of ligand binding, causing the apoptosis of the cell within hours. Caspases are cysteine-dependent aspartate-specific proteases. DRs belongs to the TNFR (Tumor Necrosis Factor Receptor) superfamily. The Fas receptor binds the transmembrane protein part of the TNF, Fas ligand. The interaction between Fas and FasL leads to the formation of Death Inducing Signaling Complex (DISC). The Complex of Fas, FADD, and procaspase8 is called the DISC.
Mechanism of the extrinsic pathway
Death receptors receive signals through receptor-ligand interactions. The receptors are FAS and TNF. This signals the adapter proteins which in combination with cytochrome C from the mitochondria give rise to initiator caspases. This leads to the formation of executioner caspases, resulting in the breakdown of the cytoskeleton and endonuclease activation. Endonuclease activation causes the fragmentation of DNA. Executioner caspases are also formed by the granzyme B inducing Cytotoxic T lymphocytes. This is followed by the formation of cytoplasmic blebs and apoptotic bodies. The apoptotic bodies have ligands for phagocytic cell receptors, facilitating phagocytosis by the phagocyte.
It is initiated by a range of exogenous and endogenous stimuli such as DNA damage, ischemia, and oxidative stress. The functional result of the pro-apoptotic signaling is mitochondrial membrane perturbation and the release of cytochrome c in the cytoplasm.
Mechanism of Intrinsic pathway
The intrinsic pathway is initiated by growth factor withdrawal, DNA damage, protein misfolding, and cell injury (by radiations, toxins, etc). This is sensed by the Bcl-2 family sensors and effecting the Bcl-2 family effectors. Bcl-2 is a human protein oncogene located on chromosome 18. Its product is a membrane integration protein and is found in the membranes of the endoplasmic reticulum and in the outer membrane of the mitochondria.
This helps in the formation of cytochrome C by the mitochondria and pro-apoptotic proteins. Cytochrome C induces the formation of initiator caspase while pro-apoptotic proteins induce the formation of executioner caspases. DNA damage resulting from the cell injury gives rise to p53, which also helps in the formation of executioner caspases. Executioner caspases aid in endonuclease activation and breakdown of the cytoskeleton. This is followed by the formation of cytoplasmic blebs and apoptotic bodies. The apoptotic bodies have ligands for phagocytic cell receptors, facilitating phagocytosis by the phagocyte.
Thus, the different pathways of apoptosis are discussed and analyzed.
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