M04.02.01 Apoptosis

Apoptosis is a physiological process in which cell death is meticulously regulated through a sequence of events. This process leads to the programmed removal of cells without harming neighboring cells. Properly executing this process is critical for maintaining tissue homeostasis, and defects in apoptosis can contribute to various diseases.

This article will explore the process of apoptosis, its regulation, and clinical conditions in which it plays a crucial role.

Pathways of Apoptosis

Apoptosis is initiated through two primary pathways:

1. Intrinsic Pathway
2. Extrinsic Pathway

Both pathways converge into a common execution phase, leading to cellular breakdown.

Intrinsic Pathway

The intrinsic pathway is triggered by internal stimuli such as:

• Biochemical stress
• DNA damage: Activates the p53 gene, which halts the cell cycle to initiate DNA repair. If the repair is unsuccessful, apoptosis is triggered.
• Lack of growth factors

Two key groups of molecules control this pathway: Bcl-2 (anti-apoptotic) and Bax (pro-apoptotic). Activation of Bax enhances apoptotic signals by forming Bax-Bax dimers, promoting apoptosis. The balance between these molecules determines whether a cell undergoes apoptosis or survives.

Extrinsic Pathway

The extrinsic pathway is initiated by external stimuli, involving the binding of specific ligands to “death” receptors on the cell surface. These receptors belong to the Tumor Necrosis Factor Receptor (TNFR) family, such as TNFR1 and FAS. Ligand binding activates downstream caspases that drive apoptosis.

Execution Phase

Once apoptosis is initiated via either the intrinsic or extrinsic pathway, it leads to the activation of caspases. These are proteolytic enzymes that exist as inactive precursors until triggered. The sequence of events includes:

• Initiator caspases (e.g., caspase 8) cleave other pro-caspases into active executioner caspases.
• Executioner caspases degrade cellular structures like the cytoskeleton and nucleus. For instance, caspase 3 activates DNAse, which fragments the DNA.
• Morphological changes occur, such as nuclear shrinkage (pyknosis) and fragmentation (karyorrhexis). The cell shrinks while maintaining its plasma membrane, forming apoptotic bodies that are later phagocytosed.

Roles of Apoptosis in Development

Apoptosis is not only vital for removing damaged cells but also plays a key role in embryonic development by shaping tissues. For example:

• Interdigital apoptosis: Separates fingers during limb development.
• Urachal cell death: Removes redundant tissue between the bladder and umbilicus.
• Neural tube closure: Apoptosis in the dorsal neural tube ensures proper closure.
• Sex differentiation: Removal of either the Müllerian or Wolffian ducts depending on fetal sex.

Failure of apoptosis in these developmental processes can lead to congenital anomalies like syndactyly, cleft palate, or spina bifida.

Regulation of Apoptosis

Apoptosis is tightly regulated by a variety of internal and external factors. These can either induce or inhibit the process, ensuring that cells only undergo apoptosis under appropriate conditions.

Table 1: Factors Influencing Apoptosis

Clinical Relevance

Syndactyly

Syndactyly, the most common congenital limb malformation, occurs in 1 in 3000 live births. It results from a failure of apoptosis, leading to fused digits.

Classification of Syndactyly

• Simple syndactyly: Fusion involves only soft tissue.
• Complex syndactyly: Fusion includes both bone and soft tissue.
• Complete syndactyly: Fusion extends to the tip of the fingers.
• Incomplete syndactyly: Fusion only partially extends to the fingertip.

Surgical intervention is often required in early childhood, especially for the most medial and lateral digits, to prevent deformities as the child grows.

Points to Remember

• Apoptosis is essential for tissue homeostasis and embryonic development.
• The process is regulated by intrinsic (internal stimuli) and extrinsic (external stimuli) pathways.
• Caspases play a central role in executing apoptosis by degrading cellular components.
• Defects in apoptosis can lead to developmental disorders like syndactyly.

Bibliography

• Elmore, S. (2007). Apoptosis: A Review of Programmed Cell Death. Toxicologic Pathology, 35(4), 495-516. Link
• Hengartner, M. O. (2000). The biochemistry of apoptosis. Nature, 407(6805), 770-776. Link