negative regulation of intrinsic apoptotic signaling pathway

Definition

Target type: biologicalprocess

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

Negative regulation of intrinsic apoptotic signaling pathway is a critical cellular process that prevents the activation of the apoptotic cascade in the absence of appropriate stimuli. This complex mechanism involves multiple regulatory steps and key players, including:

**1. Mitochondrial Membrane Permeability:**
The intrinsic apoptotic pathway is primarily regulated by the integrity of the mitochondrial outer membrane. Under normal conditions, this membrane remains impermeable to pro-apoptotic molecules like cytochrome c. However, in response to cellular stress signals, the mitochondrial membrane becomes permeable, releasing these molecules into the cytosol.

**2. Bcl-2 Family Proteins:**
A family of proteins known as Bcl-2 proteins play a central role in regulating mitochondrial membrane permeability. These proteins are classified into two main categories:
* **Anti-apoptotic Bcl-2 proteins:** These proteins, such as Bcl-2, Bcl-xL, and Mcl-1, promote cell survival by inhibiting the permeabilization of the mitochondrial membrane. They do this by binding to pro-apoptotic proteins, sequestering them and preventing their activation.
* **Pro-apoptotic Bcl-2 proteins:** These proteins, such as Bax and Bak, facilitate the permeabilization of the mitochondrial membrane in response to apoptotic stimuli. They oligomerize in the mitochondrial membrane, forming pores that allow the release of pro-apoptotic molecules.

**3. Activation of Caspase Cascade:**
Once cytochrome c is released from the mitochondria, it binds to the adaptor protein Apaf-1, initiating the formation of the apoptosome complex. The apoptosome then recruits and activates caspase-9, a key initiator caspase in the apoptotic cascade. Caspase-9, in turn, activates downstream effector caspases, such as caspase-3 and caspase-7, leading to the dismantling of the cell.

**4. Inhibition of Caspase Activation:**
Negative regulation of this pathway can occur at various points. One important mechanism involves the inhibition of caspase activation. Anti-apoptotic Bcl-2 proteins can directly bind to and inhibit the activity of caspases.

**5. Modulation of Mitochondrial Membrane Permeability:**
Another regulatory strategy focuses on preventing mitochondrial membrane permeabilization. This can involve:
* **Regulation of Bcl-2 protein expression:** Transcriptional and post-translational mechanisms can influence the expression levels of both anti- and pro-apoptotic Bcl-2 proteins, thereby tipping the balance towards cell survival or apoptosis.
* **Inhibition of Bax and Bak activation:** Various signaling pathways can activate Bax and Bak, leading to mitochondrial membrane permeabilization. Negative regulation can involve inhibiting these activation pathways, preventing Bax and Bak from forming pores in the mitochondrial membrane.

**6. Other Regulatory Mechanisms:**
Negative regulation of the intrinsic apoptotic pathway also involves other factors, such as:
* **Anti-apoptotic proteins:** Proteins like survivin and IAPs (inhibitors of apoptosis proteins) directly bind to and inhibit caspases, preventing their activation.
* **Growth factor signaling:** Certain growth factors, like epidermal growth factor (EGF) and insulin-like growth factor (IGF), can activate survival pathways that inhibit apoptotic signaling.
* **Stress response pathways:** Cells can activate stress response pathways, such as the heat shock response or the unfolded protein response, to counteract apoptotic stimuli.

**Overall, the negative regulation of the intrinsic apoptotic signaling pathway is a complex and tightly controlled process that ensures cell survival and prevents premature cell death. Dysregulation of this pathway can contribute to various diseases, including cancer and neurodegenerative disorders.**'
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Proteins (11)

Compounds (545)