Medicine & USMLE

Electron Transport Chain (ETC)

Biochemical Pathways
  1. Glycolysis
  2. Citric Acid Cycle (TCA Cycle)
  3. Electron Transport Chain (ETC)
  4. Cori Cycle
  5. De Novo Purine Synthesis
  6. De Novo Pyrimidine Synthesis
  7. Purine Salvage
  8. Purine Excretion
  9. Ethanol Metabolism
  10. Pyruvate Metabolism
  11. HMP Shunt (Pentose Phosphate Pathway)
  12. Galactose Metabolism
  13. Sorbitol (Polyol) Pathway
  14. Urea Cycle
  15. Alanine (Cahill) Cycle
  16. Catecholamine Synthesis & Breakdown
  17. Homocysteine Metabolism
  18. Fatty Acid Synthesis (Citrate Shuttle)
  19. Fatty Acid Breakdown (Carnitine Shuttle)
  20. Propionic Acid Pathway
  21. Fructose Metabolism
  22. Regulation by Fructose-2,6-Bisphosphate (F-2,6-BP)
  23. Glycogenesis
  24. Glycogenolysis


The electron transport chain, or the ETC for short, is a series of proteins found along the inner membrane of the mitochondria. The ETC plays a major role in aerobic respiration in the cell. 

There are 5 main protein complexes of the ETC to know. The first is complex I, also known as NADH dehydrogenase. Complex I receives two electrons from the high energy NADH, oxidizing the molecule to form NAD. Complex I then transfers both electrons to Ubiquinone, forming its high energy form, UQH2. The energy created through this transfer is harnessed to simultaneously pump four protons from the mitochondrial matrix into the intermembrane space. Complex I can be blocked by the actions of rotenone.

On the other hand, Complex II, also known as Succinate dehydrogenase, receives two electrons from FADH2, oxidizing the molecule to its low energy form, FAD. Like complex I, complex II transfers both of these electrons to ubiquinone, turning it into the high energy UQH2. However, unlike Complex I, Complex II does not pump any protons across the inner membrane.

Next, Complex III, also known as cytochrome reductase, transfers electrons from ubiquinone to cytochrome C. Because cytochrome C can only accept one electron at a time, two molecules of cytochrome C are actually needed to unload each ubiquinone molecule from Complex I and II. Using the energy of this reaction, Complex III also pumps four protons from the mitochondrial matrix into the intermembrane space. Complex III is blocked by the actions of antimycin A.

Afterwards, Complex IV, also known as cytochrome oxidase, then transfers electrons from Cytochrome C to oxygen, producing water as a byproduct. Through this transfer, complex IV can pump an additional two protons across the inner membrane into the intermembrane space. Complex IV can be blocked by cyanide, carbon monoxide, or by azide.

Complexes I through IV help create a proton gradient with a high concentration of protons in the intermembrane space. These protons flow down their concentration gradient to return to the mitochondrial matrix via Complex V, formally known as ATP synthase. In other words, Complex V uses the energy generated from the release of this proton gradient to create ATP! ATP is a high energy molecule used as a generic power source in the cell. This process of phosphorylating ADP to form ATP is known as oxidative phosphorylation.  Complex V can be directly blocked by the actions of oligomycin.

In addition, a few uncoupling agents work to cause leakage of protons from the intermembrane space, destroying the proton gradient and blocking the production of ATP. A few uncoupling agents to know include aspirin, thermogenin from brown fat, as well as 2,4-DNP.

Key Points

  • Electron Transport Chain (ETC)
    • Description
      • Sequence (chain) of proteins that transfers electrons
        • Electrons from NADH or FADH2, eventually transferred to O2
          • NADH and FADH2 obtained via TCA, glycolysis, or other metabolic processes
        • Uses ubiquinone and cytochromes (intermediate carriers of electrons)
      • Energetically favorable reactions
        • Creates proton gradient
        • Coupled to oxidative phosphorylation to produce ATP
    • Sequence of Steps
      • Complex I (NADH dehydrogenase)
        • Receives 2 electrons from NADH → NAD+
          • NADH obtained from TCA and other metabolic pathways
          • Transfers electrons to ubiquinone, UQ, making UQH2
            • UQ also known as Q or coenzyme Q (CoQ)
            • UQ can carry 2 electrons at a time
              • Via reduction of 2 carbonyl groups to hydroxyl groups to form an aromatic ring (ubiquinol)
            • Bypasses Complex II (only used for FADH2) to reach cytochrome reductase (Complex III)
          • Pumps 4 protons (H+) into intermembrane space
          • Inhibited by rotenone
            • Metformin is also thought to block Complex I
      • Complex II (Succinate dehydrogenase)
        • Receives 2 electrons from FADH2 → FAD
          • FAD and FADH2 derived from Vitamin B2 (Riboflavin)
          • FADH2 obtained from TCA and other metabolic pathways
          • Transfers electrons to ubiquinone, UQ (CoQ), making UQH2
            • UQ transfers 2 electrons to Complex III
          • Also converts fumarate to succinate
            • Reverse of step in tricyclic acid (TCA) cycle, which generates FADH2
          • No protons pumped across membrane
      • Complex III (Cytochrome reductase)
        • Receives electrons from QH2
          • Transfers electrons to cytochrome c
            • Reduces cytochrome c, oxidizing ubiquinone
            • Cytochrome c can only carry 1 electron at a time
              • Heme protein that cycles between a ferric and ferrous state
              • 2 cytochrome c molecules needed to unload QH2
          • Pumps 4 protons (H+) into intermembrane space
        • Inhibited by Antimycin A
      • Complex IV (Cytochrome oxidase)
        • Receives electrons from reduced cytochrome c
          • Transfers electrons to O2, making H2O
            • ½ O2 + 2H+ → H2O
            • O2 required as the final electron acceptor
              • Oxygen has the strongest attraction for electrons (most electronegativity) in the entire chain
              • In absence of oxygen, ETC stops, and cell shunts into anaerobic metabolism
          • Pumps 2 protons (H+) into intermembrane space
        • Blocked by cyanide
          • Binds to Fe3+ in cytochrome c oxidase, preventing transfer of electrons to oxygen
          • Halts ETC and aerobic respiration, leading to tissue death
        • Blocked by carbon monoxide and azide
      • Complex V (ATP Synthase)
        • Uses proton (H+) gradient generated by Complexes I - IV
          • Intermembrane space of mitochondria usually at lower pH than mitochondrial matrix due to proton gradient
          • Broken by uncoupling agents below
        • H+ from intermembrane space diffuses down its gradient across ATP synthase into mitochondrial matrix (chemiosmosis)
          • Generates ATP
            • Produces 2-3 ATP per NADH
              • Depends on whether an ATP is used to transport NADH into mitochondrial matrix
            • Produces 1-2 ATP per FADH
              • Enters later in the ETC, so less ATP generated
        • Oxidative phosphorylation couples ATP production to proton movement (chemiosmotic coupling)
        • Directly inhibited by Oligomycin
          • Does not uncouple the proton gradient, but rather inhibits the ATP synthase
    • Uncoupling Agents
      • Increase permeability of inner mitochondrial membrane to protons (H+), leading to a loss of the proton gradient
      • 2,4-dinitrophenol (DNP)
        • Used illicitly for weight loss
      • Aspirin
        • Fevers occur after overdose
      • Thermogenin
        • Found in brown fat
        • No ATP is synthesized; energy instead releases heat
          • Involved in thermogenesis (temperature maintenance), hence name: thermo-genin
          • Surgical removal of brown fat leads to hypothermia