Apoptosis is a physiological process in which cell death occurs through a regulated sequence of events. It leads to the programmed elimination of specific cells – without causing damage to surrounding tissue. Dysregulation of apoptosis contributes to a wide range of diseases, including cancer, autoimmune disorders, and developmental abnormalities. This article will explore the pathways and regulation of apoptosis, and highlight its clinical relevance. Pro Feature - 3D Model You've Discovered a Pro Feature Access our 3D Model Library Explore, cut, dissect, annotate and manipulate our 3D models to visualise anatomy in a dynamic, interactive way. Learn More 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. Adobe Stock, Licensed to TeachMeSeries LtdFig 1Intrinsic pathway of apoptosis Adobe Stock, Licensed to TeachMeSeries LtdFig 2Extrinsic 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 3Morphological 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. Apoptosis Inducers Apoptosis Inhibitors Withdrawal of growth factors Detachment from surrounding extracellular matrix Glucocorticoids Certain viruses Free radicals and oxidative stress Ionising radiation DNA damage Death receptor signalling (e.g., FAS, TNFR1) Presence of growth factors Attachment to surrounding extracellular matrix Sex steroids Viral anti-apoptotic proteins 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 4Syndactyly, webbing of the digits resulting from a failure of apoptosis Do you think you’re ready? Take the quiz below Pro Feature - Quiz Apoptosis Question 1 of 3 Submitting... Skip Next Rate question: You scored 0% Skipped: 0/3 More Questions Available Upgrade to TeachMePhysiology Pro Challenge yourself with over 1800 multiple-choice questions to reinforce learning Learn More Print Article Rate This Article