What is the Difference Between Intrinsic and Extrinsic Pathway of Apoptosis

The main difference between intrinsic and extrinsic pathway of apoptosis is the intrinsic pathway of apoptosis is activated by the intracellular pathways whereas the extrinsic pathway of apoptosis is activated by the extracellular signals.

In general, intrinsic and extrinsic pathways of apoptosis are two pathways that direct cells to programmed cell death. Apoptosis occurs in multicellular organisms to eliminate unwanted cells.  

Key Areas Covered

1. What is an Intrinsic Pathway of Apoptosis
   • Definition, Characteristics, Importance
2. What is an Extrinsic Pathway of Apoptosis
   • Definition, Characteristics, Importance
3. Similarities Between Intrinsic and Extrinsic Pathway of Apoptosis
   • Outline of Common Features
4. Difference Between Intrinsic and Extrinsic Pathway of Apoptosis
   • Comparison of Key Differences

Key Terms

Apoptosis, Extrinsic Pathway of Apoptosis, Intrinsic Pathway of Apoptosis, Cellular Stress-mediated Apoptosis, Receptor-mediated Apoptosis

What is an Intrinsic Pathway of Apoptosis

The intrinsic pathway of apoptosis is the activation of apoptosis by intracellular signals. Oncogenes, direct DNA damage, hypoxia, and survival factor deprivation can activate the intrinsic apoptotic pathway. However, p53 is the critical activator of the intrinsic pathway of apoptosis and it is a sensor of cell stress. Initially, in the intrinsic pathway, p53 activates the pro-apoptotic Bcl2 family members and represses anti-apoptotic Bcl2 proteins. In addition, other p53 targets include BAX, Noxa, and PUMA.

Figure 1: Intrinsic and Extrinsic Pathways of Apoptosis

Furthermore, p53 also activates some genes such as PTEN, APAF1, Perp, and p53AIP1, increasing the reactive oxygen species (ROS). However, the increase of ROS leads to oxidative damage to mitochondrial components. By that, the damage to mitochondrial DNA disrupts mitochondrial oxidative phosphorylation. Mitochondrial pathways are essential for multicellular life and the disruption of mitochondria ceases respiration, leading to cell death.

What is an Extrinsic Pathway of Apoptosis

The extrinsic pathway of apoptosis is the activation of apoptosis by extracellular factors. Therefore, the extracellular environment determines cell death. According to the triggering stimulus and the nature of the components involved, there are two apoptotic pathways. They are receptor-mediated apoptosis and cellular stress-mediated apoptosis.

1. Receptor-mediated apoptosis

Here, death ligands activate the receptor-mediated apoptosis. Death Receptors (DRs) are cell surface receptors that transmit apoptotic signals initiated by specific ligands and play a central role in instructive apoptosis. Moreover, these receptors activate Death Caspases (DCs) within seconds of ligand binding, causing an apoptotic demise of the cell within hours.

Figure 2: Apoptosis

2. Cellular stress-mediated apoptosis

In general, various cellular stresses activate cellular stress-mediated apoptosis. Gamma- and UV-radiation, treatment with cytotoxic drugs such as Actinomycin D, and removal of cytokines can induce this type of apoptosis. Moreover, this type of apoptotic pathway alters mitochondrial permeability.

Similarities Between Intrinsic and Extrinsic Pathway of Apoptosis

• Intrinsic and extrinsic pathways of apoptosis are two types of apoptotic pathways that lead to programmed cell death.
• Both activate cell signaling cascades that lead to cell death.
• Furthermore, these pathways are important in multicellular organisms to remove unwanted cells.

Difference Between Intrinsic and Extrinsic Pathway of Apoptosis

Definition

The intrinsic pathway of apoptosis refers to a pathway of apoptosis that involves conserved signaling proteins and is physically associated with mitochondria to drive cell apoptosis, while the extrinsic pathway of apoptosis refers to a pathway that initiates apoptosis triggered by a death ligand binding to a death receptor, such as TNF-α to TNFR1.

Determinants

Oncogenes, direct DNA damage, hypoxia, and survival factor deprivation can activate the intrinsic apoptotic pathway while the extracellular environment determines the cell death in the extrinsic pathway.

Importance

Usually, the intrinsic pathway of apoptosis is activated by the intracellular pathways while the extrinsic pathway of apoptosis is activated by the extracellular signals.

Process

The intrinsic pathway is activated by an intracellular signal generated when cells are stressed and depend on the release of proteins from the intermembrane space of mitochondria, while the extrinsic pathway is activated by extracellular ligands binding to cell-surface death receptors, which leads to the formation of the death-inducing signaling complex (DISC). 

Conclusion

In brief, the intrinsic pathway of apoptosis is the type of apoptotic pathway induced by intracellular factors such as oncogenes, direct DNA damage, hypoxia, etc., while the extrinsic pathway of apoptosis is the apoptotic pathway induced by the extracellular environment. In addition, the intrinsic pathway of apoptosis occurs through mitochondrial disruption while the extrinsic pathway involves death ligand binding pathways to activate apoptosis. However, both pathways activate the programmed cell death. Therefore, the main difference between intrinsic and extrinsic pathway of apoptosis is their apoptotic inducers and mechanisms of cell death.

References:

1. Lossi, L. (2022). The concept of intrinsic versus extrinsic apoptosis. Biochemical Journal, 479(3), 357–384. 

Image Courtesy:

1. “Control Of The Apoptosis Mecanisms” By Pierre Fauquenot & Margaux Belhassen – Own work (CC BY-SA 3.0) via Commons Wikimedia
2. “Apoptosis DU145 cells mosaic ” By Egelberg – Own Work (CC BY SA 3.0) via Commons Wikimedia