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Biochemistry · Metabolic pathway

Electron transport chain and oxidative phosphorylation !

The respiratory chain passes electrons from NADH and FADH₂ to oxygen; the energy pumps protons, and ATP synthase uses them to make most of the cell's ATP.

Updated 2026-11-01

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Key facts

  • It runs in the inner mitochondrial membrane: complexes I, III and IV pump protons as they pass electrons towards O₂, the final acceptor.
  • Two doors to ubiquinone: NADH enters at complex I and FADH₂ at complex II (succinate dehydrogenase), which pumps no protons.
  • Approximate yield: about 2.5 ATP per NADH and 1.5 ATP per FADH₂; about 30–32 ATP per fully oxidised glucose.
  • Protons pumped per electron pair from NADH: 4 (complex I) + 4 (complex III) + 2 (complex IV) = 10; each ATP costs about 4 H⁺ including phosphate transport.
  • Without O₂, or with cyanide or CO, the chain stops: NADH is not reoxidised, the Krebs cycle slows and pyruvate ends up as lactate.

Memory aid

Inhibitors by complex: “Rotenone-I, Antimycin-III, Cyanide and CO-IV, Oligomycin-V”.

Also called
Respiratory chain, Mitochondrial electron transport chain

Regulation

  • Respiratory control: electron flow depends on ADP; if the cell does not spend ATP, the high gradient slows the chain.
  • Uncouplers (UCP1, 2,4-dinitrophenol) let protons return without passing through ATP synthase: the chain speeds up and the energy leaves as heat.
  • ATP demand and the Ca²⁺ of contracting muscle activate the dehydrogenases that feed NADH to the chain.

The steps, one by one

  1. Step 1 · Complex I (NADH:ubiquinone oxidoreductase) irreversible NADH + Ubiquinone → Ubiquinol (QH₂) + NAD⁺Takes 2 electrons from NADH, passes them through FMN and a row of Fe-S clusters to ubiquinone, and pumps 4 H⁺ into the intermembrane space.If it fails: Variants in the MT-ND genes cause Leber hereditary optic neuropathy; complex I defects are the most common cause of Leigh syndrome. Leber hereditary optic neuropathy (LHON) →
  2. Step 2 · Complex III (cytochrome bc₁) irreversible Ubiquinol (QH₂) + Cytochrome c (Fe³⁺) → Cytochrome c (Fe²⁺) + UbiquinoneQ cycle: each ubiquinol gives one electron to cytochrome c through the Rieske centre and sends the other back to ubiquinone through the b hemes; 4 H⁺ are released per pair.If it fails: Variants in MT-CYB and in assembly genes such as BCS1L cause myopathy with exercise intolerance and, sometimes, Leigh syndrome.
  3. Step 3 · Complex IV (cytochrome c oxidase) irreversible Cytochrome c (Fe²⁺) + o2 → H⁺ gradient + H₂OTakes 4 electrons from 4 cytochrome c molecules, reduces one O₂ to 2 H₂O and pumps 2 H⁺ per pair: with complexes I and III it completes the gradient.If it fails: Cyanide and CO block it: the cell cannot use O₂ even when it arrives. Variants in SURF1, which assembles the complex, are a classic cause of Leigh syndrome. Cyanide poisoning →
  4. Step 4 · ATP synthase (complex V) H⁺ gradient + ADP + phosphate (Pi) ⇌ ATP in the matrix + H₂OH⁺ flow back into the matrix through the Fo channel and spin it; the rotation changes the shape of the F1 β subunits, which bind ADP and phosphate and release ATP.If it fails: MT-ATP6 variants cause NARP (neuropathy, ataxia and retinitis pigmentosa) and maternally inherited Leigh syndrome. Leigh syndrome →
  5. Step 5 · Adenine nucleotide translocase (ANT) irreversible ATP in the matrix + ADP → ATP in the cytosolExports newly made ATP to the cytosol in exchange for an incoming ADP; the swap uses part of the membrane potential. Phosphate enters on its own carrier.If it fails: SLC25A4 (ANT1) variants cause progressive external ophthalmoplegia and cardiomyopathy with myopathy.

Clinical notes

  • Cyanide and carbon monoxide block complex IV: tissue hypoxia with lactic acidosis even though the blood carries oxygen.
  • Mitochondrial diseases (MELAS, LHON, Leigh syndrome) hit the brain, retina, muscle and heart hardest, the tissues that spend the most ATP.
  • Complexes I and III are the cell's main source of superoxide; antioxidant defences keep it in check.
  • Mitochondrial DNA is inherited from the mother, and each cell can carry a mix of normal and mutant copies (heteroplasmy).

Pathways

Test yourself

Think of the answer, then tap the question to see it.

About how much ATP do one NADH and one FADH₂ yield in the respiratory chain?

About 2.5 per NADH and 1.5 per FADH₂: FADH₂ enters at complex II, which pumps no protons, and skips complex I.

Which complex of the chain pumps no protons?

Complex II (succinate dehydrogenase): it passes FADH₂'s electrons to ubiquinone without moving H⁺.

What is the final electron acceptor of the respiratory chain?

Oxygen: complex IV reduces it to water with 4 electrons and 4 protons.

Which classic inhibitor acts on each complex?

Rotenone on I, antimycin A on III, cyanide, CO and azide on IV, and oligomycin on ATP synthase.

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Educational information, not medical advice. For any symptom, see a health professional.

Sources: Respiratory electron transport (Reactome, 2026); Formation of ATP by chemiosmotic coupling (Reactome, 2026); Textbook of Biochemistry for Medical Students, 6th ed. (Jaypee Brothers Medical Publishers (Vasudevan DM, Sreekumari S, Vaidyanathan K), 2011).

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