Which of the following best distinguishes the intrinsic (mitochondrial) pathway of apoptosis from the extrinsic (death receptor) pathway?

Explanation

## Distinguishing Feature: Site of Initiation and Caspase Activation **Key Point:** The intrinsic and extrinsic apoptotic pathways differ fundamentally in their **initiation site** and the **primary caspase activated**. ### Intrinsic (Mitochondrial) Pathway - Triggered by **intracellular stress**: DNA damage, hypoxia, oxidative stress, growth factor withdrawal - **Bcl-2 family proteins** (pro-apoptotic: Bax, Bak; anti-apoptotic: Bcl-2, Bcl-xL) regulate mitochondrial outer membrane permeabilization (MOMP) - **Cytochrome c** is released from mitochondria into cytoplasm - Cytochrome c + Apaf-1 + pro-caspase-9 form the **apoptosome** - **Caspase-9** is the initiator caspase - Often p53-dependent (but not always) ### Extrinsic (Death Receptor) Pathway - Triggered by **extracellular ligand binding** to death receptors (Fas, TNF-R1, TRAIL-R) - Ligand binding recruits **DISC** (Death-Inducing Signaling Complex): death receptor + FADD + pro-caspase-8 - **Caspase-8** is the initiator caspase (activated directly at the cell surface) - Does **not require mitochondria** for initial activation - p53-independent ### Comparison Table | Feature | Intrinsic | Extrinsic | | --- | --- | --- | | **Trigger** | Intracellular stress (DNA damage, hypoxia) | Extracellular ligand (FasL, TNF-α, TRAIL) | | **Initiation site** | Mitochondria | Cell surface (death receptor) | | **Key regulator** | Bcl-2 family proteins | Death receptors (Fas, TNF-R1) | | **Initiator caspase** | Caspase-9 | Caspase-8 | | **Cytochrome c release** | Yes (MOMP) | No | | **Adapter protein** | Apaf-1 | FADD | | **p53 involvement** | Often (but not obligatory) | No | **High-Yield:** The **mitochondrial release of cytochrome c** is the hallmark discriminator of the intrinsic pathway and is absent in the extrinsic pathway. **Clinical Pearl:** Tumors often evade apoptosis by upregulating anti-apoptotic Bcl-2 (intrinsic pathway block) or downregulating death receptors (extrinsic pathway block). This is why some cancers are resistant to chemotherapy (which triggers intrinsic apoptosis) but may still respond to death receptor agonists. [cite:Robbins 10e Ch 3]