Apoptosis is a programmed form of cell death that eliminates unwanted cells through a tightly regulated cascade of caspase activation. It is essential for development, tissue homeostasis, and immune function. Dysregulation of apoptosis contributes to cancer, autoimmune disease, and neurodegeneration.
Morphological Features
Apoptotic cells display characteristic changes. The cell shrinks and condenses, chromatin aggregates against the nuclear membrane, and the nucleus fragments. The plasma membrane blebs, and the cell breaks into apoptotic bodies containing nuclear fragments and organelles. Apoptotic bodies are rapidly engulfed by phagocytes without triggering inflammation. This contrasts with necrosis, where cells swell, lyse, and release inflammatory contents.
Caspases
Caspases are cysteine-aspartic proteases that execute the apoptotic program. They are synthesized as inactive zymogens called procaspases and are activated by proteolytic cleavage. Initiator caspases, including caspase-8 and caspase-9, are activated by proximity-induced dimerization in signaling complexes. Effector caspases, including caspase-3 and caspase-7, are activated by initiator caspases and carry out the demolition phase.
Effector caspases cleave numerous cellular substrates. They inactivate inhibitors of DNase, allowing DNA fragmentation. They cleave nuclear lamins, causing nuclear disintegration. They disrupt cytoskeletal proteins, causing cell shrinkage and blebbing. They cleave ICAD, releasing CAD nuclease that fragments DNA into nucleosomal units.
The Extrinsic Pathway
The extrinsic pathway is triggered by death receptors on the cell surface. Fas ligand binds the Fas receptor, and TNF-alpha binds TNFR1. Ligand binding induces receptor trimerization and formation of the death-inducing signaling complex. Fas-associated death domain protein recruits procaspase-8 to DISC, where it is activated. Active caspase-8 then cleaves and activates effector caspases.
In some cells, caspase-8 also cleaves Bid, a BH3-only protein, generating truncated Bid that engages the mitochondrial pathway. This amplification loop is important in type II cells, where caspase-8 activation is insufficient to directly activate sufficient effector caspases. FLIP proteins inhibit caspase-8 activation at DISC and are targeted by some viruses to prevent apoptosis of infected cells.
The Intrinsic Pathway
The intrinsic or mitochondrial pathway is regulated by the Bcl-2 family of proteins, which control mitochondrial outer membrane permeabilization. The family includes pro-apoptotic BH3-only proteins such as Bid, Bad, and Bim that sense cellular stress, pro-apoptotic effector proteins Bax and Bak that form pores, and anti-apoptotic proteins Bcl-2, Bcl-xL, and Mcl-1 that inhibit Bax and Bak.
Cellular stress signals including DNA damage, growth factor withdrawal, and oncogene activation induce BH3-only proteins. BH3-only proteins neutralize anti-apoptotic Bcl-2 proteins and directly activate Bax and Bak. Activated Bax and Bak oligomerize on the outer mitochondrial membrane, forming pores that release cytochrome c and other intermembrane space proteins.
The Apoptosome
Cytochrome c released into the cytosol binds apoptotic protease activating factor-1, which oligomerizes to form the apoptosome. This wheel-like structure recruits procaspase-9, promoting its activation by dimerization. Active caspase-9 then activates caspase-3 and caspase-7, executing the apoptotic program. The X-linked inhibitor of apoptosis protein binds and inhibits caspase-9 and effector caspases. Smac-DIABLO, also released from mitochondria, neutralizes IAPs.
Regulation of Apoptosis
p53 is a central regulator of apoptosis, induced by DNA damage and oncogenic stress. It activates transcription of pro-apoptotic Bcl-2 family members including PUMA, Noxa, and Bax. p53 also has transcription-independent pro-apoptotic activities. Loss of p53 function in cancer removes this critical apoptotic barrier.
Survival signals activate PI3K-AKT signaling, which phosphorylates and inactivates Bad, promotes Mcl-1 expression, and inactivates the FOXO transcription factors that induce pro-apoptotic genes. The NF-kappaB pathway induces anti-apoptotic proteins including Bcl-xL, c-FLIP, and IAPs.
Apoptosis in Disease
In cancer, apoptosis is suppressed through multiple mechanisms. Bcl-2 is overexpressed in follicular lymphoma due to a chromosomal translocation. IAPs are frequently upregulated. p53 is mutated in over half of cancers. These defects contribute to chemoresistance. BH3 mimetics such as venetoclax, a Bcl-2 inhibitor, have transformed treatment of CLL.
Excessive apoptosis contributes to neurodegenerative diseases. In Alzheimer disease, amyloid-beta peptides induce apoptosis in neurons. Excitotoxicity in stroke activates apoptotic pathways. In autoimmune diseases, defective apoptosis of self-reactive lymphocytes contributes to autoimmunity.
Other Forms of Cell Death
Necroptosis is a programmed form of necrosis mediated by RIPK1, RIPK3, and MLKL. It is triggered when caspase-8 is inhibited, serving as a backup cell death mechanism. Necroptosis releases damage-associated molecular patterns that activate immune responses. Pyroptosis is a highly inflammatory form of programmed cell death triggered by inflammasomes, involving gasdermin D pore formation and IL-1-beta release.
