• Clinical science

Electron transport chain and oxidative phosphorylation


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.


Electron transport chain

Oxidative phosphorylation

Electron transport chain and ATP synthesis

Electron transport chain

Complex I (NADH dehydrogenase)

  • Transfers two protons (H+) and two electrons (e-) to coenzyme Q
  • NADHNAD+ + H+ + 2 e-
  • Pumps four protons into the intermembrane space

Complex II (contains succinate dehydrogenase )

  • Transfers two protons (H+) and two electrons (e-) to coenzyme Q
  • FADH2FAD + 2 H+ + 2 e-
  • Does not pump protons into the intermembrane space

Complex III (coenzyme Q-cytochrome c reductase)

  • Transfers two electrons (e-) from coenzyme Q to two molecules cytochrome c
  • Reduced coenzyme Q (QH2) + 2 H+ + 2 oxidized cytochrome c → oxidized coenzyme Q + 4 H+ + 2 reduced cytochrome c
  • Transfers 4 protons (H+) into the intermembrane space

Complex IV (cytochrome c oxidase)

Oxidative phosphorylation

Complex V (ATP synthase)

  • ADP + Pi → ATP
  • Acts as proton channel, works like a turbine → flow of protons allows generation of ATP
  • For every 4 protons one ATP is generated
  • Yield
    • 1 NADH transport of 10 H+ 2.5 ATP
    • 1 FADH2 transport of 6 H+ 1.5 ATP

Clinical significance

To remember complex 1 (rotenone) and 3 (antimycin) inhibitors, think: “one rotten carrot, three antsy (anti) mice.”

  • Kaplan. USMLE Step 1 Lecture Notes 2018: Biochemistry and Medical Genetics. New York, NY: Kaplan; 2017.
  • Chatterjea M, Shinde R. Textbook of Medical Biochemistry. New Delhi, India: JP Medical Ltd; 2011.
last updated 11/03/2020
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