Indicate the difference between intrinsic and extrinsic apoptotic pathways

Apoptosis is a highly regulated process of programmed cell death that removes unwanted or damaged cells without causing inflammation. There are two main apoptotic pathways: the intrinsic (mitochondrial) pathway and the extrinsic (death receptor) pathway. The intrinsic pathway is triggered by internal stress like DNA damage, while the extrinsic pathway is activated by external signals such as death ligands. Even though both pathways lead to programmed cell death, they are quite different in many ways. These differences are based on various criteria such as:

1. Based on Type of Triggering Signal

Intrinsic pathway is activated by internal cellular stress signals such as DNA damage, oxidative stress and ER stress. These arise from within the cell itself, usually due to damage or malfunction that threatens cell survival.

Extrinsic pathway is triggered by external signals like binding of death ligands (e.g., FasL, TNF-α) to death receptors on the plasma membrane, usually sent by immune cells to remove unwanted or infected cells.

2. Based on Initiating Mechanism and Location

Intrinsic pathway begins with mitochondrial outer membrane permeabilization (MOMP), leading to the release of cytochrome c into the cytosol. This process is highly controlled by Bcl-2 family proteins and occurs inside the cell without any ligand-receptor interaction.

Extrinsic pathway is initiated at the cell surface when death ligands bind to specific death receptors like Fas or TNFR1. This forms a death-inducing signaling complex (DISC) that activates downstream caspases.

3. Based on Initiator Caspases and Activation Complex

Intrinsic pathway uses caspase-9 as the initiator, which is activated through the formation of the apoptosome complex (Apaf-1 + cytochrome c + procaspase-9). This complex forms in the cytoplasm only after mitochondrial cytochrome c release.

Extrinsic pathway uses caspase-8 (or caspase-10 in humans) as the initiator, which is directly activated by DISC complex formed at the plasma membrane without requiring mitochondrial involvement.

4. Based on Role of Mitochondria

Intrinsic pathway is mitochondria-dependent and completely relies on mitochondrial signaling. Without mitochondrial membrane permeabilization, this pathway cannot proceed, making mitochondria the central regulator.

Extrinsic pathway is mitochondria-independent in its primary form. However, in some cells (called Type II cells), caspase-8 cleaves Bid protein, which indirectly connects it to mitochondria, forming a crosstalk with the intrinsic pathway.

5. Based on Physiological Role and Cell Type Specificity

Intrinsic pathway mainly functions in response to internal damage, like mutations and metabolic failure. It plays a major role in tumor suppression, organ development and response to stress in most mammalian cells.

Extrinsic pathway is primarily active in immune regulation, where cytotoxic T-cells and NK cells use it to kill virus-infected or cancer cells. It is more common in immune target cells like hepatocytes and lymphocytes.
Apoptosis is a highly regulated process of programmed cell death that removes unwanted or damaged cells without causing inflammation. There are two main apoptotic pathways: the intrinsic (mitochondrial) pathway and the extrinsic (death receptor) pathway. The intrinsic pathway is triggered by internal stress like DNA damage, while the extrinsic pathway is activated by external signals such as death ligands. Even though both pathways lead to programmed cell death, they are quite different in many ways. These differences are based on various criteria such as:






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