Electron transport chain and oxidative phosphorylation
Last updated: January 24, 2023
Summary![toggle arrow icon](https://manus-media.amboss.com/icons/chevron_up.svg)
Oxidative phosphorylation is a metabolic pathway through which cells release the energy stored in carbohydrates, fats, and proteins to produce adenosine triphosphate (ATP), the main source of energy for intracellular reactions. The process takes place within the mitochondria and involves oxidation-reduction reactions and the generation of an electrochemical gradient by the electron transport chain. The electron transport chain (mitochondrial respiratory chain) is embedded in the inner mitochondrial membrane and consists of four electron carrier complexes (complexes I–IV) that transfer electrons from nicotinamide adenine dinucleotide (NADH) and flavin adenine dinucleotide (FADH2) to oxygen, thereby generating water (H2O). The electron carrier complexes not only transfer electrons, but also pump protons out of the mitochondrial matrix into the mitochondrial intermembrane space, thereby creating an electrochemical gradient. Re-entry of these protons through ATP-synthase (complex V) into the mitochondrial matrix results in the phosphorylation of adenosine diphosphate (ADP) into ATP. Uncoupling agents, such as aspirin and 2,4-dinitrophenol, dissociate the electron transport chain from ATP synthesis by reducing the electrochemical gradient across the mitochondrial membrane. Oligomycin inhibits ATP synthesis by blocking the reflux of protons through ATP-synthase. In states of prolonged hypoxia (e.g., cardiac ischemia), the electron transport chain will stop running, ATP will no longer be produced, and cells may die.
![ATP Synthase: Key Enzyme of Aerobic Energy Metabolism](data:image/jpg;base64,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)
Overview![toggle arrow icon](https://manus-media.amboss.com/icons/chevron_up.svg)
Electron transport chain and ATP synthesis![toggle arrow icon](https://manus-media.amboss.com/icons/chevron_up.svg)
Clinical significance![toggle arrow icon](https://manus-media.amboss.com/icons/chevron_up.svg)
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Uncoupling agents: dissociation of the electron transport chain and ATP synthase
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Increased permeability of mitochondrial membrane → reduced proton gradient and increased oxygen consumption → electron transfer continues but ATP synthesis stops → production of heat
- Salicylic acid (in high dosages; fever commonly develops after overdose)
- 2,4-Dinitrophenol
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Thermogenin (in brown fat, which contains more mitochondria than white fat): a proton channel that physiologically uncouples electron transport and ATP synthesis to generate heat
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Respiratory chain inhibitors
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Electron transport chain inhibitors
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ATP synthase inhibitors: block ATP synthesis by stopping the electron transfer via an increased proton gradient (e.g., oligomycin)
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Prolonged tissue hypoxia (e.g., in myocardial infarction): lack of O2 molecules to accept the electrons NADH and FADH2 → disruption of the electron transport chain → decreased ATP production → cell injury or death
To remember complex 1 (rotenone) and 3 (antimycin) inhibitors, think: “one rotten carrot, three antsy (anti) mice.”
![Mechanism of action: respiratory chain inhibitors](data:image/jpeg;base64,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)
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