Intrinsic vs Extrinsic Apoptosis: Pathways and Key Differences
Explore the intrinsic and extrinsic apoptosis pathways, their molecular signals, and regulatory mechanisms that control programmed cell death.
Cells have a built-in mechanism to eliminate themselves when they are damaged, infected, or no longer needed. This process, known as apoptosis, is essential for maintaining tissue health and preventing diseases such as cancer and autoimmune disorders. Apoptosis occurs through two main pathways: intrinsic and extrinsic, each triggered by different signals and regulated by distinct molecular mechanisms.
Mitochondrial Signals In Intrinsic Pathway
The intrinsic pathway is governed by mitochondrial signals that regulate cell death in response to internal stressors like DNA damage, oxidative stress, and growth factor deprivation. When a cell detects these disturbances, it activates a sequence of molecular events culminating in mitochondrial outer membrane permeabilization (MOMP), a decisive step in apoptosis.
MOMP is controlled by the Bcl-2 family of proteins, which include both pro-apoptotic and anti-apoptotic members. Pro-apoptotic proteins like Bax and Bak undergo conformational changes, oligomerize, and insert into the mitochondrial membrane, forming pores that release cytochrome c and other apoptogenic factors. Anti-apoptotic proteins such as Bcl-2 and Bcl-xL inhibit this process. BH3-only proteins, including Bid, Bim, and Puma, promote apoptosis by neutralizing anti-apoptotic factors.
Once in the cytoplasm, cytochrome c binds to apoptotic protease activating factor-1 (Apaf-1), forming the apoptosome, which activates procaspase-9. This initiates a caspase cascade that dismantles the cell. Other mitochondrial factors, such as Smac/DIABLO and Omi/HtrA2, inhibit inhibitor of apoptosis proteins (IAPs), ensuring the process is irreversible and leads to complete cellular disassembly.
Death Receptors In Extrinsic Pathway
The extrinsic pathway is initiated by death receptors, a subset of the tumor necrosis factor receptor (TNFR) superfamily that transduces extracellular death signals. These receptors, embedded in the plasma membrane, are activated by ligands such as tumor necrosis factor (TNF), Fas ligand (FasL), and TNF-related apoptosis-inducing ligand (TRAIL). Ligand binding induces receptor trimerization, exposing cytoplasmic death domains that recruit adaptor proteins and trigger apoptosis.
A well-characterized example involves Fas (CD95) and FasL. When FasL binds to Fas, receptor trimerization occurs, leading to the recruitment of the adaptor protein Fas-associated death domain (FADD). FADD then binds procaspase-8, forming the death-inducing signaling complex (DISC). DISC facilitates procaspase-8 activation, which initiates the extrinsic pathway.
Activated caspase-8 directly processes executioner caspases such as caspase-3 and caspase-7, leading to cellular breakdown. In some cells, the extrinsic pathway requires mitochondrial amplification. This occurs when caspase-8 cleaves Bid into tBid, which translocates to the mitochondria and promotes apoptogenic factor release, linking the extrinsic and intrinsic pathways.
Role Of Caspase Cascades
Caspases, a family of cysteine-aspartic proteases, execute apoptosis by dismantling cellular components. Synthesized as inactive zymogens (procaspases), they require proteolytic cleavage for activation. Initiator caspases like caspase-8 and caspase-9 activate executioner caspases such as caspase-3, caspase-6, and caspase-7, ensuring apoptosis proceeds irreversibly.
Executioner caspases cleave key intracellular substrates, driving the morphological and biochemical changes characteristic of apoptosis. One primary target is poly(ADP-ribose) polymerase (PARP), an enzyme involved in DNA repair. PARP cleavage prevents futile repair attempts, conserving energy for cell disassembly. Caspases also degrade structural proteins like lamin A/C, leading to chromatin condensation and nuclear fragmentation. Additionally, they activate DNases that fragment DNA, creating the hallmark DNA laddering pattern of apoptosis.
Beyond structural degradation, caspases facilitate apoptotic debris removal. By cleaving inhibitor of caspase-activated DNase (ICAD), they enable chromosomal DNA degradation. They also disrupt cytoskeletal proteins such as actin and tubulin, causing cell shrinkage and membrane blebbing. These changes promote apoptotic body formation, ensuring efficient phagocyte clearance and preventing inflammation.
Key Differences In Regulation
The intrinsic and extrinsic pathways differ in regulation, each relying on distinct molecular checkpoints. The intrinsic pathway is governed by intracellular stress sensors that assess cellular damage before initiating apoptosis. The balance between pro-apoptotic and anti-apoptotic Bcl-2 family proteins determines mitochondrial permeability and cell fate. Because it integrates multiple stress signals, the intrinsic pathway ensures apoptosis occurs only when necessary.
The extrinsic pathway, in contrast, is regulated by extracellular stimuli, with death receptor activation as the primary control point. Sensitivity to apoptotic signals is influenced by ligand availability, receptor density, and decoy receptors. Inhibitory proteins like c-FLIP, which resembles caspase-8 but lacks enzymatic activity, prevent unintended apoptosis. This regulation ensures apoptosis occurs under appropriate physiological conditions, such as immune surveillance or tissue remodeling.