negative regulation of oxidative stress-induced neuron intrinsic apoptotic signaling pathway

Definition

Target type: biologicalprocess

Any process that stops, prevents or reduces the frequency, rate or extent of oxidative stress-induced neuron intrinsic apoptotic signaling pathway. [GO_REF:0000058, GOC:bf, GOC:PARL, GOC:TermGenie, PMID:15790595]

Negative regulation of oxidative stress-induced neuron intrinsic apoptotic signaling pathway involves a complex interplay of molecular mechanisms aimed at mitigating the damaging effects of reactive oxygen species (ROS) on neuronal cells. ROS, generated as byproducts of normal cellular metabolism or in response to environmental stressors, can disrupt cellular homeostasis and induce apoptosis, a programmed cell death process. To counter this threat, neurons have evolved intricate defense strategies.

**1. Anti-oxidant Defense:**

* **Enzymatic Antioxidants:** Key enzymes like superoxide dismutase (SOD), catalase, and glutathione peroxidase (GPx) neutralize ROS by converting them to less harmful molecules. SOD catalyzes the dismutation of superoxide radicals into hydrogen peroxide, which is then further broken down by catalase or GPx into water and oxygen.
* **Non-Enzymatic Antioxidants:** Molecules such as glutathione, vitamin C (ascorbic acid), and vitamin E (α-tocopherol) act as scavengers of ROS, directly interacting with free radicals and preventing their damaging effects.

**2. Signaling Pathway Modulation:**

* **Nuclear Factor Erythroid 2-Related Factor 2 (Nrf2):** Nrf2 is a transcription factor that plays a pivotal role in orchestrating the cellular response to oxidative stress. Upon ROS accumulation, Nrf2 translocates to the nucleus and activates the expression of genes encoding antioxidant enzymes and proteins involved in detoxification.
* **Mitogen-Activated Protein Kinases (MAPKs):** MAPKs, such as ERK, JNK, and p38, are signaling cascades that can be activated by ROS. While some MAPKs promote apoptotic signaling, others like ERK can act as survival pathways, promoting antioxidant defenses and cell survival.
* **PI3K/Akt Pathway:** This pathway is crucial for cell survival and growth. Upon activation by growth factors or other stimuli, PI3K activates Akt, which phosphorylates and inhibits pro-apoptotic proteins like Bad and Bax.

**3. Mitochondrial Integrity:**

* **Mitochondrial Dynamics:** Fusion and fission processes help maintain mitochondrial function and limit the accumulation of damaged mitochondria, which are major ROS sources.
* **Mitochondrial Membrane Potential:** The mitochondrial membrane potential is essential for ATP production. Oxidative stress can disrupt this potential, leading to dysfunction. However, mechanisms exist to restore it, including the activation of mitochondrial uncoupling proteins, which dissipate the proton gradient across the inner mitochondrial membrane.

**4. DNA Repair:**

* **DNA Damage Response (DDR):** ROS can damage DNA, leading to mutations and apoptosis. To counteract this, cells have evolved sophisticated DDR pathways involving DNA repair enzymes, checkpoint kinases, and other proteins.

**5. Chaperone Proteins:**

* **Heat Shock Proteins (HSPs):** These proteins assist in the correct folding and assembly of other proteins, preventing aggregation and promoting cellular homeostasis. They also contribute to the clearance of misfolded or damaged proteins.

**6. Apoptosis Inhibition:**

* **Bcl-2 Family Proteins:** The Bcl-2 family comprises both pro-apoptotic (Bax, Bak) and anti-apoptotic (Bcl-2, Bcl-xL) proteins. Under oxidative stress, anti-apoptotic Bcl-2 proteins can counteract the effects of pro-apoptotic proteins, preventing the release of cytochrome c from mitochondria, a key step in the apoptotic cascade.

**Conclusion:**

Negative regulation of oxidative stress-induced neuron intrinsic apoptotic signaling pathway involves a multi-faceted response encompassing antioxidant defenses, signaling pathway modulation, mitochondrial integrity maintenance, DNA repair, chaperone protein activity, and inhibition of apoptotic cascades. These processes work in concert to mitigate ROS-induced damage, protect neuronal cells from apoptosis, and ensure proper neuronal function.
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Proteins (4)

Compounds (49)