What is apoptosis ? What are its stages ? Write about the molecular mechanism of apoptosis.

What is Apoptosis?

Apoptosis is a genetically programmed process of cellular self-destruction that is essential for the development and maintenance of multicellular organisms. It differs from necrosis in several key aspects:

• Apoptosis: Controlled, energy-dependent, non-inflammatory, characterized by cell shrinkage, DNA fragmentation, and formation of apoptotic bodies.
• Necrosis: Uncontrolled, energy-independent, inflammatory, characterized by cell swelling, membrane rupture, and release of cellular contents.

Stages of Apoptosis

Apoptosis unfolds in a series of distinct stages:

1. Initiation Stage

This stage involves receiving a signal to initiate the apoptotic pathway. This signal can be either extrinsic or intrinsic.

• Extrinsic Pathway (Death Receptor Pathway): Triggered by the binding of ligands (e.g., TNF-α, Fas ligand) to death receptors (e.g., TNFR1, Fas) on the cell surface. This activates intracellular signaling cascades.
• Intrinsic Pathway (Mitochondrial Pathway): Initiated by intracellular stress signals like DNA damage, oxidative stress, or growth factor withdrawal. These signals lead to mitochondrial outer membrane permeabilization (MOMP).

2. Regulation Stage

This stage involves the activation of regulatory proteins that determine whether the apoptotic signal will proceed.

• Bcl-2 Family Proteins: These proteins play a crucial role in regulating MOMP. Pro-apoptotic members (e.g., Bax, Bak) promote MOMP, while anti-apoptotic members (e.g., Bcl-2, Bcl-xL) inhibit it.
• IAPs (Inhibitor of Apoptosis Proteins): These proteins directly inhibit caspases, preventing the execution of apoptosis.

3. Execution Stage

This stage involves the activation of caspases, a family of cysteine proteases, which dismantle the cell.

• Initiator Caspases (e.g., Caspase-8, Caspase-9): Activated by the initiation signals. They then activate effector caspases.
• Effector Caspases (e.g., Caspase-3, Caspase-7): Execute the apoptotic program by cleaving various cellular substrates, leading to DNA fragmentation, cytoskeletal breakdown, and cell dismantling.

Molecular Mechanism of Apoptosis

The molecular mechanisms underlying apoptosis are complex and involve a cascade of events.

Intrinsic Pathway – Detailed Mechanism

1. Mitochondrial Permeabilization: Intracellular stress leads to the activation of pro-apoptotic BH3-only proteins (e.g., Bid, Bim, Puma).
2. Cytochrome c Release: These proteins antagonize anti-apoptotic Bcl-2 family members, allowing Bax and Bak to oligomerize and form pores in the mitochondrial outer membrane, releasing cytochrome c into the cytoplasm.
3. Apoptosome Formation: Cytochrome c binds to Apaf-1 and pro-caspase-9, forming the apoptosome.
4. Caspase Activation: The apoptosome activates caspase-9, which in turn activates effector caspases (caspase-3 and caspase-7).

Extrinsic Pathway – Detailed Mechanism

1. Death Receptor Activation: Ligand binding to death receptors recruits adaptor proteins (e.g., FADD).
2. DISC Formation: FADD recruits pro-caspase-8, forming the Death-Inducing Signaling Complex (DISC).
3. Caspase-8 Activation: Within the DISC, pro-caspase-8 is activated to caspase-8.
4. Effector Caspase Activation: Caspase-8 directly activates effector caspases or activates Bid, linking the extrinsic and intrinsic pathways.

Pathway	Initiating Signal	Key Molecules	Outcome
Intrinsic	Intracellular Stress	Bcl-2 family, Cytochrome c, Apaf-1, Caspase-9	Mitochondrial permeabilization, Apoptosome formation, Caspase activation
Extrinsic	Death Receptor Ligand Binding	Death Receptors, FADD, Caspase-8	DISC formation, Caspase activation