Major concepts:

1. Where does electron transport occur, and why is that important?
2. What enzymes catalyze the reactions of electron transport? How is proton transport related to electron transport, and how is it different?
3. Given the reduction potentials of the molecules involved, can you write a balanced redox reaction and calculate ΔE°′ and ΔG°′ for the reaction? How do you know whether or not the reaction is spontaneous?
4. What molecules, in what order, are required to move 2 e⁻ from NADH to O₂? To move 2 e⁻ from succinate to O₂?
5. How is pH related to ΔG_T for the inner mitochondrial membrane?

Core knowledge

1. What are the characteristics of the inner mitochondrial membrane?
2. What are cytochromes? How do they differ from each other, and how are they alike?
3. How many electrons are involved in an oxidation-reduction reaction that includes NADH, or Q, or cytochromes, or O₂?
4. For each complex involved in electron transport, what is oxidized, what is reduced, and how many H⁺ are moved from N to P for each reaction?
5. What equation relates ΔE°′ and ΔG°′?
6. What are uncouplers, and why are they important?

Mitochondrial structure
outer porous membrane allows free movement of smaller solutes (ions, metabolites)
inner membrane is impermeable except to H₂O, O₂, and CO₂.
     include electron transport complexes and ATP synthase
intermembrane space = P (positive) side of the inner membrane (has higher [H⁺]
matrix = enzymes of citric acid cycle, pyruvate dehydrogenase complex, and others
matrix side of the inner membrane = N (negative) side (lower [H⁺]

Overview of electron transport, a part of oxidative phosphorylation:
A series of oxidation-reduction reactions (e⁻ transfer) is coupled to proton (H⁺) transport.
This creates a proton gradient which can be used to provide energy for ATP synthesis.

Coenzymes and proteins involved in electron transport
NAD⁺: transfers 2 e⁻ with H⁺ (= H⁻); other H⁺ involved in the redox reaction is released
FAD: can transfer 1 or 2 e⁻ with 2 H⁺; stays tightly bound
Ubiquinone (Q): can transfer 1 or 2 e⁻:
     Q + H⁺ + e⁻ ↔ QH·⁻ + H⁺ + e⁻ ↔ QH₂
     has a long nonpolar tail, making it soluble in the membrane
cytochromes: proteins + heme-like molecules (coenzymes) with Fe²⁺
     cyt (Fe³⁺) + e⁻ ↔ cyt (Fe²⁺) – transfers 1 e⁻
     different types of cytochromes vary in side chains of the porphyrin ring
         absorption spectra of cytochromes vary from one to another
              also vary between oxidized and reduced forms
     most are integral membrane proteins; cyt c is a peripheral membrane protein
ISP = iron-sulfur protein, with Fe coordinated by –S–Cys–protein
     number of S and number of Fe varies, depending on the protein
     transfer 1 e⁻ (even if there is more than 1 Fe, only 1 Fe in the cluster is oxidized/reduced)

Four complexes of the electron transport chain;
function originally determined by studying the effects of inhibitors

Complex I = NADH-ubiquinone oxidoreductase (NADH dehydrogenase)
overall reaction: NADH + H⁺ + Q ↔ NAD⁺ + QH₂
      ΔE°′ = 0.045 + 0.320 = 0.365 V
      ΔG°′ = − n F ΔE°′ = − 70.4 kJ/mol (theoretically enough to synthesize 2 ATP)
components: FMN and iron-sulfur proteins
function:
      1. NADH on N side of the membrane is oxidized
     2. intermediate oxidation-reduction reactions involve FMN and iron-sulfur proteins
     3. 4 H⁺ are moved from the N side to the P side during the intermediate reactions
     4. Q is reduced to QH₂ and leaves Complex I

Complex II = succinate dehydrogenase (part of the citric acid cycle)
overall reaction: succinate + Q ↔ fumarate + QH₂
      ΔE°′ = 0.045 - 0.031 = 0.014 V
      ΔG°′ = − (2) (96485 J/V-mol) (0.014 V) = − 2.7 kJ/mol (not enough to synthesize ATP)
components: FAD and iron-sulfur proteins
function:
      1. succinate in the matrix is oxidized and FAD is reduced
     2. FAD is regenerated by the reduction of Q
     3. No H⁺ cross the membrane

Complex III = ubiquinone/cytochrome c oxidoreductase
overall reaction: QH₂ + 2 cyt c (Fe³⁺) ↔ Q + 2 cyt c (Fe²⁺) + 2 H⁺
     ΔE°′ = 0.254 - 0.045 = 0.209 V
     ΔG°′ = − 2 (96485 J/V-mol) (0.209 V) = − 40.3 kJ/mol
components: Rieske ISP (= iron-sulfur protein), cyt c₁, cyt b_L, cyt b_H,
     2 different Q-binding sites: Q_P on the P side of the membrane, and Q_N on the matrix side
function involves 2 cycles
     1^st cycle overall reaction: QH₂ + cyt c (Fe³⁺) → Q·⁻ + cyt c (Fe²⁺) + 2 H⁺_P
         1. QH₂ (P site) is oxidized by cyt c₁, releasing 2 H⁺ on the P side, → cyt c 1 (Fe²⁺) + Q·⁻
         2. Q·⁻ is oxidized by cyt b_L → Q + cyt b_L (red)
         3. cyt b_L (red) is oxidized by cyt b_H (ox) → cyt b_L (ox) + cyt b_H (red)
         4. cyt b_H (red) is oxidized by Q (N site) → cyt b_H (ox) + Q·
     2^nd cycle overall reaction: QH₂ + Q·⁻ + cyt c (Fe³⁺) + 2 H⁺ → QH₂ + Q + cyt c (Fe 2+ ) + 2 H⁺_P
         1. QH₂ (P site) is oxidized by cyt c₁, releasing 2 H⁺ on the P side, → cyt c 1 (Fe²⁺) + Q·⁻
         2. Q·⁻ is oxidized by cyt b_L → Q + cyt b_L (red)
         3. cyt b_L (red) is oxidized by cyt b_H (ox) → cyt b_L (ox) + cyt b_H (red)
         4. cyt b_H (red) is oxidized by Q·⁻ (N site) + 2 H⁺ → cyt b_H (ox) + QH₂
     overall reaction: 1 QH₂ completely oxidized, 2 cyt c reduced, 4 H⁺ moved to P side

Complex IV = cytochrome oxidase
overall reaction: 4 cyt c (Fe²⁺) + 4 H⁺ + O₂ → 4 cyt c (Fe³⁺) + 2 H₂O
     ΔE°′ = 0.816 V − 0.254 V = 0.562 V
     ΔG°′ = − (1) (96485 J/V-mol) (0.562 V) = − 54.2 kJ/mol
components: two centers with Cu complexed with S = Cu_A and Cu_B, cyt a, cyt a₃
function: a complex series of reactions involving transfer of e⁻ from 4 cyt c
      actually involves oxidation states of O₂, not O
     intermediates complexed to cyt a₃ and Cu_B
     4 H⁺ pumped across the membrane for 4 e⁻ transferred

Remember that NADH transfer = 2 e⁻, so for each NADH oxidized,
Complex I moves 4 H⁺
Complex III moves 4 H⁺
Complex IV moves 2 H⁺ = total of 10 H⁺

For each succinate oxidized,
Complex II moves 0 H⁺
Complex III moves 4 H⁺
Complex IV moves 2 H⁺ = total of 6 H⁺

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