Apoptosis

Apoptosis Pathways

Apoptosis can be initiated via two main routes: the intrinsic pathway and the extrinsic pathway. Both ultimately converge on a common execution phase, resulting in controlled cell death.

Intrinsic Pathway

The intrinsic pathway triggers apoptosis in response to internal stimuli:

• Biochemical stress – disruptions in normal cellular metabolism (e.g., oxidative stress or misfolded protein accumulation) that can overwhelm the cell’s repair mechanisms.
• DNA damage – this activates the p53 gene, which halts the cell cycle and initiates DNA repair. If this repair attempt is unsuccessful, apoptosis can be induced.
• Withdrawal of growth factors – the absence of essential survival signals which normally inhibit apoptotic pathways.

This pathway is tightly regulated by the Bcl-2 protein family, which includes both pro-apoptotic (e.g., Bax, Bak) and anti-apoptotic (e.g., Bcl-2, Bcl-XL) members. The balance between these proteins acts as a molecular switch, determining whether a cell will survive or undergo apoptosis.

Extrinsic Pathway

The extrinsic pathway of apoptosis is initiated by external stimuli – primarily through the binding of ligands to death receptors on the cell surface.

Key receptors include members of the Tumour Necrosis Factor Receptor (TNFR) superfamily, such as FAS and TNFR1. Ligand binding to these receptors activates initiator caspases, triggering the downstream execution phase.

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Fig 1
Intrinsic pathway of apoptosis

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Fig 2
Extrinsic pathway of apoptosis

Execution Phase

The execution phase is the final common pathway of apoptosis, in which activated enzymes dismantle the cell in an orderly and controlled manner.

Both intrinsic and extrinsic pathways activate initiator caspases (e.g., caspase-8 or caspase-9), which in turn cleave and activate executioner caspases (e.g., caspase-3, -6, -7).

These executioner caspases dismantle the cell by degrading structural and nuclear components. For instance, caspase-3 activates DNAse – leading to fragmentation of DNA.

The key morphological changes in apoptosis include:

• Chromatin condensation (pyknosis)
• Nuclear fragmentation (karyorrhexis)
• Apoptotic body formation

Importantly, the cell membrane remains intact, reducing inflammation. Apoptotic bodies are eventually cleared by phagocytes.

By TeachMeSeries Ltd (2025)

Fig 3
Morphological changes during apoptosis

Roles of Apoptosis

Beyond its role in removing damaged or harmful cells, apoptosis is essential in foetal development, helping to sculpt and refine tissues.

• Interdigital apoptosis – allowing separation of fingers and toes
• Regression of the urachus – removing the redundant channel between the bladder and umbilicus
• Removal of Müllerian or Wolffian ducts – aiding sex-specific reproductive development
• Apoptosis in the dorsal neural tube – allowing proper closure during neural tube formation
• Loss of redundant palatal epithelium – permitting fusion of the palatal shelves in the developing mouth

Failure of apoptosis during development can result in structural malformations such as syndactyly, cleft palate, or spina bifida.

Regulation of Apoptosis

Apoptosis is finely controlled by a range of signals, which may be intracellular or extracellular. Disruption in these can lead to excessive or insufficient cell death, contributing to disease.

Clinical Relevance

Syndactyly

Syndactyly is the most common congenital limb anomaly, affecting approximately 1 in 3,000 live births. It results from incomplete apoptosis during limb development, leading to fusion of adjacent digits.

In normal development, the human hand initially forms as a paddle-like structure. Apoptosis sculpts the hand by initiating cell death in the tissue between the developing fingers (known as interdigital rays). This creates clear separation between the digits.

When this process is disrupted, the tissue between the fingers fails to regress, resulting in syndactyly—the fusion of two or more digits.

Syndactyly can be classified by its appearance:

• Simple – digits joined only by soft tissue

• Complex – fusion involves bones or nails

• Complete – fusion extends to the fingertip

• Incomplete – partial fusion of digits

By Dumplestilskin, uploaded by Gliu (en.wiki, uploaded under same name) [Public domain], via Wikimedia Commons

Fig 4
Syndactyly, webbing of the digits resulting from a failure of apoptosis