Regarding the intrinsic and extrinsic pathways of apoptosis, all of the following statements are correct EXCEPT:

Question

Accepted Answer

A. The intrinsic pathway is initiated by direct activation of caspase-8 in response to mitochondrial outer membrane permeabilization. ## Apoptotic Pathways: Intrinsic vs Extrinsic

### Extrinsic Pathway (Death Receptor-Mediated)
**Key Point:** Initiated by extracellular ligands binding to death receptors (Fas, TNF-R1, TRAIL-R).
- Ligand binding recruits adaptor proteins (FADD) and procaspase-8
- Forms the Death-Inducing Signaling Complex (DISC)
- Direct activation of caspase-8 → caspase-3 activation

### Intrinsic Pathway (Mitochondrial)
**Key Point:** Triggered by intracellular stress (DNA damage, hypoxia, oxidative stress, growth factor withdrawal).
- Regulated by Bcl-2 family proteins (pro-apoptotic: Bax, Bak; anti-apoptotic: Bcl-2, Bcl-xL)
- Results in mitochondrial outer membrane permeabilization (MOMP)
- Releases cytochrome c from mitochondria
- Cytochrome c binds Apaf-1 → forms apoptosome
- Apoptosome recruits and activates procaspase-9
- Caspase-9 then activates caspase-3

### Convergence Point
**High-Yield:** Both pathways converge at **caspase-3**, the final executioner caspase.
- Caspase-3 cleaves PARP, lamin A/C, and other substrates
- Results in DNA fragmentation, chromatin condensation, and apoptotic body formation

### Why the Incorrect Statement is Wrong
The intrinsic pathway does **NOT** directly activate caspase-8. Instead:
1. Cellular stress → MOMP
2. Cytochrome c release → apoptosome formation
3. Apoptosome activates caspase-9 (not caspase-8)
4. Caspase-9 then activates caspase-3

Caspase-8 is the initiator caspase of the **extrinsic** pathway only. The intrinsic pathway uses caspase-9 as its initiator caspase.

### Comparison Table

| Feature | Extrinsic | Intrinsic |
| --- | --- | --- |
| **Trigger** | Death receptor ligation | Cellular stress (DNA damage, hypoxia) |
| **Key Regulator** | Death receptors (Fas, TNF-R1) | Bcl-2 family proteins |
| **Initiator Caspase** | Caspase-8 | Caspase-9 |
| **Mechanism** | DISC formation | MOMP → cytochrome c release → apoptosome |
| **Convergence** | Caspase-3 | Caspase-3 |
| **Speed** | Faster | Slower |

[cite:Robbins 10e Ch 2]

Answer

B. The extrinsic pathway is initiated by binding of ligands to death receptors such as Fas and TNF receptor 1

Answer

C. Both pathways converge at the level of caspase-3 activation, which is the final executioner caspase

Answer

D. The intrinsic pathway is regulated by Bcl-2 family proteins and is triggered by cellular stress including DNA damage and hypoxia

Regarding the intrinsic and extrinsic pathways of apoptosis, all of the following statements are correct EXCEPT:

Explanation

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