Electron Transport Chain (ETC) & ATP Synthesis

Overview

Diagram 1 — Components of the Respiratory Chain

Components of the electron transport chain showing NADH:CoQ oxidoreductase (Complex I), Succinate dehydrogenase (Complex II), Cytochrome b-c₁ complex (Complex III), and Cytochrome c oxidase (Complex IV). — Basic Medical Biochemistry, 6e

Components of the Respiratory Chain (Complexes I–IV)

• Coenzyme Q (CoQ / Ubiquinone): Lipid-soluble; shuttles electrons from Complex I and II (and glycerol-3-phosphate dehydrogenase, acyl-CoA dehydrogenase) to Complex III
• Cytochrome c: Water-soluble; peripheral to the inner mitochondrial membrane; shuttles electrons from Complex III to Complex IV

Diagram 2 — ETC with Proton Pumping & ATP Synthesis

ETC showing proton pumping at Complexes I (4H⁺), III (4H⁺), and IV (2H⁺). Ten H⁺ are pumped per NADH oxidized. Complex V (ATP synthase) uses the gradient to synthesize ATP. — Lippincott Illustrated Reviews: Biochemistry, 8e

ATP Formation — Chemiosmotic Hypothesis (Mitchell Hypothesis)

Mechanism

1. Proton pump: As electrons pass through Complexes I, III, and IV, energy released drives pumping of H⁺ from the matrix to the intermembrane space (IMS).
   • 10 H⁺ pumped per NADH oxidized (4+4+2)
   • 6 H⁺ pumped per FADH₂ oxidized (0+4+2, entering via CoQ)
2. Electrochemical gradient (Proton-Motive Force): This creates:
   • An electrical gradient (positive charge accumulates in IMS)
   • A pH gradient (IMS is more acidic than matrix)
   • Together = proton-motive force (~220 mV)
3. ATP synthase (Complex V): H⁺ re-enter the matrix through the F₀ channel, driving rotation of the c-ring. This rotational energy is transmitted to the F₁ domain, where conformational changes in the three β subunits cyclically:
   • Bind ADP + Pᵢ
   • Catalyze phosphorylation (ATP synthesis)
   • Release ATP
   • One full rotation = 3 ATP; ~3–4 H⁺ needed per ATP

Binding Change Mechanism (Boyer)

ATP Synthesis Sites

• Glycolysis: ~2 ATP (net) + 2 NADH (cytosolic)
• Pyruvate decarboxylation: 2 NADH
• TCA cycle: 6 NADH + 2 FADH₂ + 2 GTP
• Grand total: ~30–32 ATP per glucose

Diagram 3 — Full ETC with ROS Generation

Full ETC showing electron flow, proton pumping, ATP export via VDAC, and superoxide (O₂•⁻) generation at Complexes I and III

Inhibitors of the ETC

A. ETC Electron Transport Inhibitors (Block specific complexes)

B. ATP Synthase (Phosphorylation) Inhibitors

C. Uncouplers of Oxidative Phosphorylation

Respiratory Control

• High ADP → faster electron transport, more O₂ consumption, more ATP synthesis
• Low ADP → electron transport slows (rate-limiting step is H⁺ re-entry through ATP synthase)
• Oligomycin locks mitochondria in a state of low electron transport despite adequate substrate

Summary: Sites of Action

NADH → [Complex I] → CoQ ← [Complex II] ← FADH₂
                              ↓
                    [Complex III] → Cyt c
                                        ↓
                              [Complex IV] → H₂O
                                    ↓
                         H⁺ gradient (proton-motive force)
                                    ↓
                           [Complex V / ATP Synthase]
                                    ↓
                                  ATP

Inhibitors:          Uncouplers:
 I  — Rotenone       DNP, Thermogenin (UCP1)
 III — Antimycin A   Salicylates (high dose)
 IV — CN⁻, CO, N₃⁻
 V  — Oligomycin

• Lippincott Illustrated Reviews: Biochemistry, 8th ed. pp. 224–243
• Basic Medical Biochemistry: A Clinical Approach, 6e. pp. 860–878