Medicine & USMLE

Electron Transport Chain (ETC)

  1. Citric Acid Cycle (TCA, Krebs)
  2. Glycolysis - Investment Phase
  3. Glycolysis - Payoff Phase
  4. Pentose Phosphate Pathway - Oxidative Phase
  5. Pentose Phosphate Pathway - Non-Oxidative Phase
  6. Glycogenesis
  7. Glycogenolysis
  8. Gluconeogenesis
  9. Electron Transport Chain (ETC)


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. 

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. 

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. 

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. 

Key Points

  • Electron Transport Chain (ETC)
    • Description
      • Sequence (chain) of proteins that transfers electrons
        • Electrons from NADH or FADH2, eventually transferred to O2
        • Uses ubiquinone and cytochromes (intermediate carriers of electrons)
        • Remember for electron transfer, oxidation is loss of electrons, while reduction is gain of elections
          • Mnemonic: OIL RIG
      • Energetically favorable reactions
        • Creates proton gradient that is used to indirectly produce energy (ATP)
    • Sequence of Steps
      • Complex I (NADH dehydrogenase)
        • Receives 2 electrons from NADH → NAD+
          • NADH obtained from TCA and other metabolic pathways and is oxidized in this reaction
        • Transfers electrons to ubiquinone (Q) making QH2
          • Q also known as UQ or coenzyme Q (CoQ)
          • Q 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
      • Complex II (Succinate dehydrogenase)
        • Receives 2 electrons from FADH2 → FAD
          • FADH2 obtained from TCA and other metabolic pathways
        • Transfers electrons to ubiquinone (Q) making QH2
          • Q 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 to restore QH2 to Q
          • 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
      • 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
      • 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
        • 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
        • Couples phosphorylation of ADP → ATP to proton movement
          • Called chemiosmotic coupling, a form of oxidative phosphorylation