response to hypoxia

Definition

Target type: biologicalprocess

Any process that results in a change in state or activity of a cell or an organism (in terms of movement, secretion, enzyme production, gene expression, etc.) as a result of a stimulus indicating lowered oxygen tension. Hypoxia, defined as a decline in O2 levels below normoxic levels of 20.8 - 20.95%, results in metabolic adaptation at both the cellular and organismal level. [GOC:hjd]

Hypoxia, or oxygen deficiency, is a fundamental stressor that triggers a complex and multifaceted cellular response aimed at maintaining homeostasis and survival. This response involves multiple signaling pathways and transcriptional regulatory networks, resulting in a cascade of physiological and biochemical adaptations.

**1. Sensing Oxygen Depletion:**

- **Hypoxia-Inducible Factors (HIFs):** Key transcription factors that act as oxygen sensors. HIFs are heterodimers composed of an α subunit (HIF-1α, HIF-2α, or HIF-3α) and a constitutively expressed β subunit (ARNT). Under normoxic conditions, HIF-α subunits are hydroxylated by prolyl hydroxylases (PHDs), leading to their ubiquitination and degradation by the proteasome. However, in hypoxic conditions, PHD activity is inhibited, allowing HIF-α to accumulate and translocate to the nucleus.

**2. Transcriptional Regulation by HIFs:**

- **Glycolytic Pathway Activation:** HIFs stimulate the transcription of genes involved in glycolysis, the primary pathway for ATP production in the absence of oxygen. This includes enzymes like hexokinase, phosphofructokinase, and lactate dehydrogenase, which promote glucose uptake and anaerobic metabolism.
- **Angiogenesis Induction:** HIFs promote the formation of new blood vessels by inducing the expression of vascular endothelial growth factor (VEGF). VEGF acts on endothelial cells, stimulating their proliferation, migration, and tube formation.
- **Erythropoiesis Stimulation:** HIFs activate the transcription of erythropoietin (EPO), a hormone that stimulates red blood cell production in the bone marrow. This increases the oxygen-carrying capacity of the blood.
- **Cellular Survival and Proliferation:** HIFs regulate the expression of genes involved in cell survival, apoptosis, and proliferation. They can promote cell survival by inhibiting apoptosis and enhancing cell proliferation under hypoxic conditions.
- **Cellular Adaptation and Remodeling:** HIFs can induce the expression of genes involved in cellular adaptation to chronic hypoxia, including those involved in mitochondrial biogenesis, autophagy, and metabolic reprogramming.

**3. Other Cellular Responses:**

- **Reactive Oxygen Species (ROS) Production:** Hypoxia can lead to increased ROS production due to impaired mitochondrial respiration. While ROS can contribute to cellular damage, they also play a signaling role in the hypoxic response.
- **Mitochondrial Adaptations:** Hypoxia triggers mitochondrial adaptation, including changes in mitochondrial morphology, biogenesis, and function. These adaptations aim to optimize energy production under limited oxygen availability.
- **Cellular Metabolism and Bioenergetics:** Hypoxia profoundly impacts cellular metabolism, shifting from oxidative phosphorylation to glycolysis for ATP production. This metabolic switch is crucial for maintaining cellular energy supply under hypoxic conditions.

**4. Pathological Consequences:**

- **Ischemia:** Prolonged or severe hypoxia can lead to tissue ischemia, a condition where the blood supply to a tissue is insufficient, causing cell damage and death.
- **Cancer:** Hypoxia plays a crucial role in tumor growth and metastasis. Cancer cells adapt to hypoxic conditions, promoting their survival, proliferation, and invasion.
- **Chronic Diseases:** Chronic hypoxia is associated with various diseases, including cardiovascular disease, pulmonary disease, and neurological disorders.

**5. Therapeutic Implications:**

- **Drug Development:** The hypoxic response pathway presents a target for drug development, particularly in the treatment of cancer and ischemic diseases.
- **Gene Therapy:** Targeting HIFs or other key players in the hypoxic response pathway holds potential for gene therapy approaches.

Overall, the response to hypoxia is a complex and highly regulated process that ensures cellular survival and adaptation in the face of oxygen deprivation. Understanding this intricate network of signaling pathways and transcriptional responses is crucial for unraveling the underlying mechanisms of various diseases and developing effective therapies.'
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Proteins (86)

Compounds (2,591)