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Apoptosis is caused by signals that switch on a set of protein-cutting enzymes called caspases. Those signals come from two directions: death receptors on the cell surface (the extrinsic pathway) and stress or loss of survival signals that act through the mitochondria (the intrinsic pathway). Both pathways converge on executioner caspases, and once caspases are activated the commitment to cell death appears irreversible.
Short answer
Cells die by apoptosis when either of two kinds of signal reaches them. An external ligand binding a death receptor such as Fas or a TNF receptor starts the extrinsic pathway. Withdrawal of growth factors, hormones or cytokines, or DNA damage from irradiation or chemotherapy drugs in some cells, starts the intrinsic pathway through the mitochondria. In both cases caspases carry out the dismantling of the cell.
Definition and scope
The NHGRI Genetics Glossary defines apoptosis as “the process of programmed cell death.” It is used during early development to eliminate unwanted cells, and in adults it is used to rid the body of cells that have been damaged beyond repair. So apoptosis is a normal, regulated process, not only a response to injury. When it is blocked in a damaged cell, that cell can keep dividing, which is why the process is tied to tumor biology.
This guide explains what triggers the process and how those triggers are wired to the execution machinery. For the bench readouts that detect apoptotic cells, see the CASRAI guides on the Annexin V/PI apoptosis assay and the TUNEL assay. For the wider field, see what cell biology covers.
How apoptosis is triggered
The extrinsic pathway: death receptors
According to the review by Elmore (Toxicologic Pathology, 2007), the extrinsic signaling pathways that initiate apoptosis involve transmembrane receptor-mediated interactions. Death receptors such as Fas and the TNF receptors bind their ligands at the cell surface. The adaptor protein FADD then associates with procaspase-8, which brings the first caspase of this pathway into play.
The intrinsic pathway: mitochondria
The intrinsic pathway starts inside the cell. Stimuli change the inner mitochondrial membrane, and cytochrome c is released. Per Elmore, cytochrome c binds and activates Apaf-1 as well as procaspase-9, forming a structure called the apoptosome. The stimuli can be negative, meaning the absence of growth factors, hormones or cytokines, and the review notes that irradiation and chemotherapy drugs cause DNA damage that can trigger the pathway in some cells.
The caspase cascade
Caspases are described by Elmore as having proteolytic activity, able to cleave proteins at aspartic acid residues. Once they are initially activated, there seems to be an irreversible commitment towards cell death. Initiator caspases switch on executioner caspases, and the executioners do the cutting.
The Bcl-2 family: gatekeepers of the mitochondria
The Bcl-2 family of proteins governs mitochondrial membrane permeability and can be either pro-apoptotic or anti-apoptotic. Reports cited by Elmore indicate that Bcl-2 and Bcl-XL inhibit apoptotic death primarily by controlling the activation of caspase proteases.
Cause-to-pathway checklist
This cross-walk maps each trigger described above to its pathway and first caspase, so you can work from an experimental treatment to the expected route. Every row is taken from the Elmore review.
| Trigger | Pathway | First caspase involved |
|---|---|---|
| Ligand binding a death receptor (Fas, TNF receptors), with FADD recruited | Extrinsic | Caspase-8 (procaspase-8) |
| Absence of growth factors, hormones or cytokines | Intrinsic (mitochondrial) | Caspase-9 (via the apoptosome) |
| DNA damage from irradiation or chemotherapy drugs, in some cells | Intrinsic (mitochondrial) | Caspase-9 (via the apoptosome) |
Types of caspases
Elmore groups the caspases by role, which tells you which family member to expect at which step.
| Group | Members named in the review |
|---|---|
| Initiators | Caspase-2, -8, -9, -10 |
| Executioners | Caspase-3, -6, -7 |
| Inflammatory | Caspase-1, -4, -5 |
Where it matters for labs
When cells are treated with a death ligand, deprived of growth factors, or exposed to a DNA-damaging agent, the trigger indicates which pathway and which initiator caspase to expect. Two CASRAI guides cover common readouts: the Annexin V/PI assay run on a flow cytometer, and the TUNEL assay. For viability measurements often run alongside them, see the MTT assay guide and the hemocytometer counting guide.
Common misunderstandings
- Apoptosis is not only a disease process. The NHGRI glossary describes it as part of early development and as routine removal of damaged adult cells.
- Caspases are proteases, not kinases. They cleave proteins at aspartic acid residues.
- The Bcl-2 family is not uniformly protective. Members can be pro-apoptotic or anti-apoptotic.
FAQ
What causes apoptosis in a cell?
Either a death-receptor signal at the cell surface (extrinsic) or loss of survival signals and DNA damage acting through the mitochondria (intrinsic). Both lead to caspase activation.
What is the difference between the extrinsic and intrinsic pathways?
The extrinsic pathway begins with receptors such as Fas or TNF receptors and involves caspase-8. The intrinsic pathway begins at the mitochondria, with cytochrome c, Apaf-1 and the apoptosome involving caspase-9.
Can chemotherapy or radiation cause apoptosis?
Elmore reports that irradiation and chemotherapy drugs cause DNA damage that can trigger apoptosis in some cells.
Is apoptosis reversible?
After caspases are initially activated, the review states there seems to be an irreversible commitment towards cell death.
Sources
- NHGRI Genetics Glossary, “Apoptosis”: genome.gov/genetics-glossary/Apoptosis (checked 2026-10-29).
- Elmore S. “Apoptosis: A Review of Programmed Cell Death.” Toxicologic Pathology, 2007: PMC2117903 (checked 2026-10-29).
