negative regulation of hypoxia-induced intrinsic apoptotic signaling pathway

Definition

Target type: biologicalprocess

Any process that stops, prevents or reduces the frequency, rate or extent of hypoxia-induced intrinsic apoptotic signaling pathway. [GO_REF:0000058, GOC:bf, GOC:PARL, GOC:TermGenie, PMID:24553947]

Negative regulation of hypoxia-induced intrinsic apoptotic signaling pathway is a complex process that involves a series of molecular events designed to prevent cell death under oxygen-deprived conditions. Hypoxia, or a state of low oxygen availability, triggers a cellular stress response that can lead to programmed cell death, or apoptosis. The intrinsic apoptotic pathway, also known as the mitochondrial pathway, is one of the major pathways involved in this process.

**Key Players and Mechanisms:**

1. **Hypoxia-Inducible Factors (HIFs):** HIFs are transcription factors that are stabilized under hypoxic conditions. HIFs bind to specific DNA sequences in the promoter regions of genes involved in cellular adaptation to hypoxia, including genes involved in angiogenesis (formation of new blood vessels), glycolysis (energy production without oxygen), and cell survival.

2. **Mitochondrial Membrane Potential (MMP):** Hypoxia can disrupt the mitochondrial membrane potential, leading to the release of pro-apoptotic proteins such as cytochrome c. This release initiates the caspase cascade, a series of enzymatic reactions that ultimately lead to cell death.

3. **Anti-Apoptotic Proteins:** In response to hypoxia, cells can activate anti-apoptotic proteins, such as Bcl-2 and Bcl-xL, which prevent the release of cytochrome c from mitochondria.

4. **Apoptosis Inhibitory Proteins (AIPs):** AIPs are proteins that specifically block the activity of caspases, thereby preventing the execution of apoptosis.

5. **Autophagy:** Hypoxia can induce autophagy, a cellular process in which cells degrade and recycle their own components to survive under nutrient-limited conditions.

**Mechanism of Negative Regulation:**

* **HIFs:** HIFs can activate the expression of genes encoding anti-apoptotic proteins, such as Bcl-2 and Bcl-xL. This activation counteracts the pro-apoptotic effects of hypoxia.
* **Mitochondrial Membrane Potential:** Cells can maintain MMP by activating energy production pathways, such as glycolysis, or by enhancing the activity of the electron transport chain.
* **Anti-Apoptotic Proteins:** Bcl-2 and Bcl-xL can bind to pro-apoptotic proteins, such as Bax and Bak, and prevent them from forming pores in the mitochondrial membrane, thus blocking cytochrome c release.
* **AIPs:** AIPs can directly interact with and inhibit the activity of caspases, preventing the execution of apoptosis.
* **Autophagy:** Autophagy can provide cells with nutrients and energy under hypoxic conditions, thereby promoting survival.

**Significance:**

The negative regulation of hypoxia-induced intrinsic apoptotic signaling pathway is crucial for the survival of cells in oxygen-deprived environments. This process allows cells to adapt to hypoxia and maintain their functionality, which is essential for tissue homeostasis and organism survival.

**Dysregulation and Disease:**

Dysregulation of the negative regulation of hypoxia-induced intrinsic apoptotic signaling pathway can contribute to various diseases, including cancer. In cancer, cells can evade apoptosis under hypoxic conditions, allowing them to survive and proliferate, contributing to tumor growth and metastasis.
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