negative regulation of oxidative phosphorylation

Definition

Target type: biologicalprocess

Any process that decreases the frequency, rate or extent of the chemical reactions and pathways resulting in the phosphorylation of ADP to ATP that accompanies the oxidation of a metabolite through the operation of the respiratory chain. Oxidation of compounds establishes a proton gradient across the membrane, providing the energy for ATP synthesis. [GOC:BHF]

Negative regulation of oxidative phosphorylation is a complex biological process that involves a multitude of regulatory mechanisms to control the rate of ATP production through the electron transport chain. This process is crucial for maintaining cellular energy homeostasis and preventing oxidative stress. Key mechanisms involved in negative regulation include:

1. **Regulation of Electron Transport Chain Complexes:**
- **Inhibition of Complex I (NADH dehydrogenase):**
- **Rotenone:** A potent inhibitor of Complex I, blocking electron transfer from NADH to ubiquinone.
- **Amytal:** Another inhibitor of Complex I, acting at a different site than rotenone.
- **Inhibition of Complex III (cytochrome bc1 complex):**
- **Antimycin A:** Blocks electron flow from ubiquinol to cytochrome c.
- **Inhibition of Complex IV (cytochrome c oxidase):**
- **Cyanide:** Binds to the heme iron in cytochrome a3, preventing oxygen reduction.
- **Carbon monoxide:** Binds to the heme iron in cytochrome a3, blocking oxygen reduction.
- **Azide:** Binds to the heme iron in cytochrome a3, blocking oxygen reduction.
2. **Regulation of Proton Gradient:**
- **Uncoupling Agents:**
- **2,4-dinitrophenol (DNP):** Dissipates the proton gradient across the inner mitochondrial membrane, reducing ATP synthesis.
- **FCCP (carbonyl cyanide p-trifluoromethoxyphenylhydrazone):** A protonophore that carries protons across the mitochondrial membrane, uncoupling ATP synthesis from electron transport.
3. **Regulation of Substrate Availability:**
- **NADH/NAD+ Ratio:**
- High NADH/NAD+ ratio can inhibit Complex I activity, reducing electron flow through the chain.
- **ADP/ATP Ratio:**
- High ATP levels can feedback inhibit oxidative phosphorylation by reducing the availability of ADP, a necessary substrate for ATP synthesis.
4. **Regulation by Cellular Signaling Pathways:**
- **AMPK (AMP-activated protein kinase):**
- Activated by low cellular energy levels (high AMP/ATP ratio), AMPK inhibits oxidative phosphorylation to conserve energy.
- **Reactive Oxygen Species (ROS):**
- High levels of ROS can activate signaling pathways that negatively regulate oxidative phosphorylation.
5. **Regulation by Protein Modifications:**
- **Phosphorylation:**
- Phosphorylation of specific proteins involved in oxidative phosphorylation can alter their activity.
- **Acetylation:**
- Acetylation of specific proteins can also regulate their activity.
6. **Regulation by Gene Expression:**
- Transcription factors can regulate the expression of genes encoding proteins involved in oxidative phosphorylation.

Negative regulation of oxidative phosphorylation is a complex and dynamic process, and its dysregulation can contribute to various pathological conditions, including cancer, neurodegenerative diseases, and aging. Understanding the mechanisms involved in this process is crucial for developing therapeutic strategies for these diseases.
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Proteins (3)

Compounds (22)