[Durgical](https://durgical.com/en/) › [DurgiPedia](https://durgical.com/en/durgipedia/) › [General pathology](https://durgical.com/en/general-pathology/) › [Cell injury, adaptation and death](https://durgical.com/en/general-pathology/#a-injury) › Apoptosis: the intrinsic and extrinsic pathways [General pathology](https://durgical.com/en/general-pathology/) · [Cell injury, adaptation and death](https://durgical.com/en/general-pathology/#a-injury) # Apoptosis: the intrinsic and extrinsic pathways - Mechanism Apoptosis is a tidy, programmed suicide: the cell shrinks, cuts itself into packets and is eaten without causing inflammation. Updated 2026-11-01 ## Key points - Intrinsic (mitochondrial) pathway: BAX and BAK open the outer membrane, cytochrome c leaves, the apoptosome activates caspase 9. - BCL-2 and BCL-XL block the intrinsic pathway; BH3-only proteins (BIM, PUMA, NOXA, BAD) sense stress and favour death. - Extrinsic (death receptor) pathway: Fas ligand or TNF bind receptors, FADD recruits and activates caspase 8. - Executioner caspases 3, 6 and 7 cut the cytoskeleton and nuclear proteins and activate DNA cleavage. - t(14;18) in follicular lymphoma overexpresses BCL-2; FAS defects cause autoimmune lymphoproliferative syndrome. ## What it is Apoptosis is a regulated program of cell death that needs energy and is carried out by enzymes called caspases. It removes cells during development, ends immune responses, deletes self-reactive lymphocytes and eliminates cells with damaged DNA or misfolded proteins. Too little apoptosis favours cancer and autoimmunity; too much contributes to neurodegeneration and tissue loss. ## Key facts - Physiologic examples: loss of the webs between fingers, shedding of the endometrium, thymic negative selection, death of neutrophils after inflammation. - Cytotoxic T cells and NK cells kill by Fas ligand and by perforin plus granzyme B, which activates caspases directly. - Viral hepatitis shows single dead hepatocytes as eosinophilic apoptotic (Councilman) bodies. - Failure to clear apoptotic debris is thought to feed autoantibody formation in lupus. ## Structure - Single, scattered cells, not sheets. - Small cell with dense, deeply eosinophilic cytoplasm. - Pyknotic or fragmented nucleus; sometimes a clear halo around the cell. - No surrounding inflammatory infiltrate. ## Step by step - A trigger appears: DNA damage, growth factor withdrawal, misfolded proteins, or a death ligand on another cell. - Intrinsic: p53 and other sensors activate BH3-only proteins, which overcome BCL-2 and free BAX and BAK. - BAX and BAK make the mitochondrial outer membrane leaky; cytochrome c enters the cytosol. - Cytochrome c binds APAF-1 to form the apoptosome, which activates caspase 9. - Extrinsic: Fas ligand or TNF engage receptors; the adaptor FADD activates caspase 8 (which can also cleave BID to recruit the mitochondria). - Both routes activate executioner caspases 3, 6 and 7. - The cell shrinks, the chromatin condenses and breaks, and the cell buds into apoptotic bodies. - Phosphatidylserine flips to the outer membrane and phagocytes engulf the bodies without inflammation. ## Clinical notes - BCL-2 inhibitors are used in some lymphoid leukemias to restore apoptosis. - Many chemotherapy drugs and radiation work by damaging DNA and triggering p53-dependent apoptosis. ## Memory aid Inside or outside: the mitochondria pull the alarm from within (caspase 9), death receptors ring the doorbell from without (caspase 8); both call the same cleaners (caspase 3). ## Test yourself Think of the answer, then tap the question to see it. ## What does cytochrome c do once it is released from mitochondria? It binds APAF-1 to form the apoptosome, which activates caspase 9 and then the executioner caspases. ## Which caspase starts the extrinsic pathway? Caspase 8, activated through the adaptor FADD after Fas or TNF receptor engagement. ## Which translocation causes BCL-2 overexpression and in which tumour? t(14;18), which places BCL-2 next to the immunoglobulin heavy chain locus, in follicular lymphoma. ## Why does apoptosis not cause inflammation? The membrane stays intact and the apoptotic bodies display phosphatidylserine, so phagocytes remove them before contents leak. [Add to my cards (4)](https://durgical.app/estudiar/?add=/en/general-pathology/apoptosis-the-intrinsic-and-extrinsic-pathways/) ## Related - [Apoptosis vs necrosis: the comparison table](https://durgical.com/en/general-pathology/apoptosis-vs-necrosis-the-comparison-table/) - [Other forms of cell death: necroptosis, pyroptosis, ferroptosis](https://durgical.com/en/general-pathology/other-forms-of-cell-death-necroptosis-pyroptosis-ferroptosis/) - [Endoplasmic reticulum stress and the unfolded protein response](https://durgical.com/en/general-pathology/endoplasmic-reticulum-stress-and-the-unfolded-protein-response/) - [Evading cell death and replicating without limit: BCL2 and telomerase](https://durgical.com/en/general-pathology/evading-cell-death-and-replicating-without-limit-bcl2-and-telomerase/) - [Tumour suppressor genes: RB, TP53, APC, BRCA and the two-hit hypothesis](https://durgical.com/en/general-pathology/tumour-suppressor-genes-rb-tp53-apc-brca-and-the-two-hit-hypothesis/) - [Atrophy](https://durgical.com/en/general-pathology/atrophy/) ## Related conditions - [Non-Hodgkin lymphoma](https://durgical.com/en/conditions/non-hodgkin-lymphoma/) - [Chronic lymphocytic leukaemia](https://durgical.com/en/conditions/chronic-lymphocytic-leukaemia/) - [Viral hepatitis](https://durgical.com/en/conditions/viral-hepatitis/) - [Graft-versus-host disease](https://durgical.com/en/conditions/graft-versus-host-disease/) - [Systemic lupus erythematosus](https://durgical.com/en/conditions/systemic-lupus-erythematosus/) - [HIV infection and AIDS](https://durgical.com/en/conditions/hiv-infection-and-aids/) - [Alzheimer disease](https://durgical.com/en/conditions/alzheimer-disease/) - [Parkinson disease](https://durgical.com/en/conditions/parkinson-disease/) ## Elsewhere in DurgiPedia - [Cell injury, apoptosis and necrosis](https://durgical.com/en/histology/cell-injury-apoptosis-and-necrosis/) - [CD8⁺ cytotoxic T cell](https://durgical.com/en/immunology/cd8-cytotoxic-t-cell/) - [Natural killer cell](https://durgical.com/en/immunology/natural-killer-cell/) - [Immune tolerance and how autoimmunity begins](https://durgical.com/en/immunology/immune-tolerance-and-how-autoimmunity-begins/) - [TNF-α](https://durgical.com/en/immunology/tnf/) - [Cytochrome c](https://durgical.com/en/biochemistry/enzymes/cytochrome-c/) - [Oncogenes and tumour suppressor genes](https://durgical.com/en/biochemistry/topics/oncogenes-and-tumour-suppressor-genes/) - [Limb development: the apical ectodermal ridge, ZPA and limb rotation](https://durgical.com/en/embryology/limb-development-the-apical-ectodermal-ridge-zpa-and-limb-rotation/) [← All of general pathology](https://durgical.com/en/general-pathology/) Educational content on the mechanisms of disease; not a diagnostic or treatment guide and no substitute for a health professional's advice. No doses are given. Sources: [Autoimmune lymphoproliferative syndrome: MedlinePlus Genetics](https://medlineplus.gov/genetics/condition/autoimmune-lymphoproliferative-syndrome/) (MedlinePlus, US National Library of Medicine, 2024); [4.6 Tissue Injury and Aging](https://openstax.org/books/anatomy-and-physiology-2e/pages/4-6-tissue-injury-and-aging) (OpenStax (Rice University), 2022). ## **Spotted a mistake?** We are always improving for the community. Tell us what is wrong and our team will review it. Report a mistake Representative model, for educational purposes only. --- Source: https://durgical.com/en/general-pathology/apoptosis-the-intrinsic-and-extrinsic-pathways/ License: CC BY 4.0 (https://creativecommons.org/licenses/by/4.0/). Cite as: DurgiPedia (durgical.com), https://durgical.com/en/general-pathology/apoptosis-the-intrinsic-and-extrinsic-pathways/