What is the Difference Between Intrinsic and Extrinsic Pathway of Apoptosis

The key difference between intrinsic and extrinsic pathway of apoptosis is that the intrinsic pathway of apoptosis begins when an injury occurs within the cell and the resultant stress activates the apoptosis, while the extrinsic pathway of apoptosis begins when conditions in the extracellular environment determine that the cell must die and activates apoptosis.

Apoptosis is known as natural cell death. There are two pathways for this process; intrinsic and extrinsic pathways of apoptosis. Both these pathways are naturally occurring processes and direct the cell to programmed cell death.

CONTENTS

1. Overview and Key Difference
2. What is the Intrinsic Pathway of Apoptosis
3. What is the Extrinsic Pathway of Apoptosis
4. Similarities – Intrinsic and Extrinsic Pathway of Apoptosis
5. Intrinsic vs Extrinsic Pathway of Apoptosis in Tabular Form
6. Summary – Intrinsic vs Extrinsic Pathway of Apoptosis

What is the Intrinsic Pathway of Apoptosis?

The intrinsic pathway of apoptosis begins when there is an injury within the cell, and resulting stress activates the apoptosis mechanism. This pathway is also known as the mitochondrial pathway. During cell stress, factors like nitric oxide increase mitochondrial permeability. During this, cytochrome C is released from mitochondria through the actions of proteins such as Bax and Bak. Cytochrome C then binds with apoptotic protease activating factor (Apaf-1) and ATP. Later, all these proteins again bind to procaspase 9 to make a complex called apoptosome. The apoptosome cleaves procaspase to its active form called caspase 9, which in turn cleaves and activates procaspase into the effector caspase 3. Ultimately, effector caspase 3 catalyzes specific cleavages of key cellular proteins, leading to cell degradation.

Furthermore, mitochondria also release SMACs (second mitochondria-derived activator of caspases) into the cytosol of the cell, following the increase of permeability of the mitochondria membrane. SMACs bind to proteins that inhibit apoptosis called IAPs. This leads to the deactivation of IAPs and prevents IAPs from arresting apoptosis, allowing programmed cell death.

What is the Extrinsic Pathway of Apoptosis?

The extrinsic pathway of apoptosis begins outside the cell. It occurs when conditions in the extracellular environment determine that the cell must die. The extrinsic pathway of apoptosis further divides into two pathways: TNF (tumor necrosis factor) induced model and Fa-Fas ligand-mediated model. In TNF induced model, TNF alpha plays an important role. TNF alpha is a cytokine produced mainly by activated macrophages. The binding of TNF alpha to its receptors, such as TNFR1 and TNFR2 initiates caspase activation via the intermediate membrane proteins. Caspase activation ultimately leads to programmed cell death.

Furthermore, in the Fas pathway, the Fas receptor binds to the Fas ligand (Fasl). The binding of Fas and FasL together results in the formation of a death-inducing signaling complex (DISC). This complex contains FADD, caspase 8, and caspase 10. DISC complex executes the programmed cell death in the Fas pathway.

What are the Similarities Between Intrinsic and Extrinsic Pathway of Apoptosis?

• Intrinsic and extrinsic pathways of apoptosis are two pathways that activate programmed cell death.
• Both are natural processes.
• Both pathways are executed through specific protein complexes.
• These pathways lead to the activation of caspases that execute cell death.
• Changes to these pathways can cause diseases in humans.

What is the Difference Between Intrinsic and Extrinsic Pathway of Apoptosis?

The intrinsic pathway of apoptosis begins when there is an injury within the cell, and resulting stress activates apoptosis, while the extrinsic pathway of apoptosis begins when conditions in the extracellular environment determine that the cell must die and activates apoptosis. Thus, this is the key difference between intrinsic and extrinsic pathway of apoptosis. Furthermore, the intrinsic pathway of apoptosis is triggered by intrinsic stresses such as oncogenes, DNA damage, direct DNA damage, hypoxia, and survival factor deprivation. On the other hand, the extrinsic pathway of apoptosis is triggered by external environmental signals such as gamma and UV radiation, treatment with cytotoxic drugs like actinomycin D, and removal of cytokines.

The below infographic presents the differences between intrinsic and extrinsic pathway of apoptosis in tabular form for side-by-side comparison.

Summary – Intrinsic vs Extrinsic Pathway of Apoptosis

Apoptosis is the programmed cell death in which a series of molecular steps in a cell lead to its death. Through this method, the body gets rid of unneeded or abnormal cells. Apoptosis is of two types: intrinsic and extrinsic pathways of apoptosis. The intrinsic pathway of apoptosis begins when an injury occurs within the cell, and resulting stress activates the apoptosis mechanism, while the extrinsic pathway of apoptosis begins when conditions in the extracellular environment determine that the cell must die and activates the apoptosis mechanism. So, this summarizes the difference between intrinsic and extrinsic pathway of apoptosis.

Reference:

1. Elmore, Susan. “Apoptosis: A Review of Programmed Cell Death.” Toxicologic Pathology, U.S. National Library of Medicine, June 2007.
2. “Biochemistry, Extrinsic Pathway of Apoptosis.” StatPearls. NCBI Bookshelf.

Image Courtesy:

1. “Extrinsic and intrinsic pathways to caspase-3 activation” By Harrington HA, Ho KL, Ghosh S, Tung KC – Construction and analysis of a modular model of caspase activation in apoptosis (CC BY 2.5) via Commons Wikimedia
2. “Extrinsic apoptosis.” By B1357M – Own work (CC BY-SA 3.0) via Commons Wikimedia