regulation of intrinsic apoptotic signaling pathway

Definition

Target type: biologicalprocess

Any process that modulates the frequency, rate or extent of intrinsic apoptotic signaling pathway. [GOC:mtg_apoptosis]

The intrinsic apoptotic signaling pathway, also known as the mitochondrial pathway, is a key mechanism for programmed cell death. It is activated by a variety of cellular stresses, including DNA damage, hypoxia, and growth factor deprivation. When these stresses occur, a complex series of events is initiated, leading to the release of pro-apoptotic molecules from the mitochondria into the cytosol. This culminates in the activation of caspase cascades, ultimately leading to the dismantling of the cell.

Here is a detailed description of the key events involved in the regulation of the intrinsic apoptotic signaling pathway:

1. **Stress Signal Reception:**
- Various cellular stresses activate sensors, such as p53, ATM, and ATR, triggering the accumulation of pro-apoptotic proteins like Bax and Bak.
- These sensors can also directly activate the downstream effector protein, BH3-only proteins, which play a crucial role in activating the mitochondrial apoptotic pathway.

2. **Mitochondrial Outer Membrane Permeabilization (MOMP):**
- Activated BH3-only proteins (e.g., Bid, Bim, Puma, Noxa) bind to and activate Bax and Bak, promoting their oligomerization and formation of pores in the mitochondrial outer membrane.
- This permeabilization allows the release of pro-apoptotic molecules from the intermembrane space into the cytosol.

3. **Release of Apoptotic Factors:**
- The mitochondrial intermembrane space contains key pro-apoptotic molecules, including cytochrome c, Smac/DIABLO, and AIF.
- Upon MOMP, these factors are released into the cytosol, where they trigger downstream apoptotic signaling events.

4. **Caspase Activation:**
- Cytochrome c released from the mitochondria binds to the adaptor protein Apaf-1. This complex then recruits and activates caspase-9, a key initiator caspase.
- Activated caspase-9, in turn, activates downstream effector caspases (caspase-3, -6, and -7), which execute the apoptotic program.

5. **Execution of Apoptosis:**
- Activated effector caspases dismantle the cell by cleaving critical cellular components, including:
- Structural proteins (e.g., lamin, actin)
- DNA repair enzymes
- Proteases
- Nuclear factors
- This ultimately leads to the characteristic features of apoptosis, such as DNA fragmentation, chromatin condensation, and cell shrinkage.

6. **Regulation of the Pathway:**
- The intrinsic apoptotic signaling pathway is tightly regulated by a complex network of pro-survival and anti-apoptotic factors.
- **Pro-survival proteins:** These proteins (e.g., Bcl-2, Bcl-xL) inhibit the activation of Bax and Bak, preventing MOMP.
- **Anti-apoptotic proteins:** These proteins (e.g., IAPs) block caspase activation, preventing the execution of apoptosis.

7. **Inhibition of Apoptosis:**
- The intrinsic apoptotic pathway can be inhibited by various mechanisms, including:
- **Activation of pro-survival pathways:** Signals that stimulate cell growth or survival can activate pro-survival proteins, preventing the initiation of apoptosis.
- **Inhibition of pro-apoptotic factors:** Some proteins can directly bind to and inhibit the activity of pro-apoptotic factors, such as BH3-only proteins or caspases.
- **Induction of anti-apoptotic proteins:** Some cellular stresses can induce the expression of anti-apoptotic proteins, which can then block the activation of caspase cascades.

In summary, the intrinsic apoptotic signaling pathway is a highly regulated process that is crucial for maintaining cellular homeostasis and eliminating damaged or unwanted cells. The balance between pro-survival and pro-apoptotic signals determines whether a cell lives or dies. This pathway is tightly controlled by a complex network of proteins that regulate the permeabilization of the mitochondrial outer membrane, the release of pro-apoptotic factors, and the activation of caspase cascades.'
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Proteins (2)

Compounds (81)