The electron transport chain (ETC) is a crucial process in cellular respiration. It involves protein complexes in the inner mitochondrial membrane that transfer electrons, creating a proton gradient. This gradient drives ATP synthesis, linking the ETC to oxidative phosphorylation.

Oxidative phosphorylation produces ATP using the energy from the proton gradient. ATP synthase, driven by proton flow, catalyzes ATP production. This process is tightly regulated and can be affected by various factors, including metabolic regulators and inhibitors.

Electron Transport Chain in Respiration

Components and Function of the ETC

• Electron transport chain comprises protein complexes embedded in inner mitochondrial membrane
• Four major protein complexes transfer electrons
  • Complex I (NADH dehydrogenase)
  • Complex II (succinate dehydrogenase)
  • Complex III (cytochrome bc1 complex)
  • Complex IV (cytochrome c oxidase)
• Electrons move through complexes via redox reactions
• Oxygen serves as final electron acceptor at Complex IV

Electron Donors and Energy Production

• NADH and FADH2 act as primary electron donors to ETC
  • Produced during glycolysis, fatty acid oxidation, and citric acid cycle
• Energy released during electron transfer pumps protons from mitochondrial matrix to intermembrane space
• Proton pumping creates electrochemical gradient across inner mitochondrial membrane
• Gradient drives ATP synthesis via ATP synthase, coupling ETC to oxidative phosphorylation

Oxidative Phosphorylation and Electron Transport

ATP Synthesis Mechanism

• ATP synthase (Complex V) catalyzes ATP production using energy from proton gradient
• Proton-motive force drives protons through ATP synthase
  • Consists of proton concentration gradient and electrical potential difference
• Proton flow causes rotation of enzyme's central stalk
• Rotation induces conformational changes in catalytic sites
• Conformational changes facilitate ATP synthesis from ADP and inorganic phosphate

Efficiency and Coupling

• P/O ratio represents ATP molecules produced per electron pair transferred through ETC
  • Theoretical maximum of ~2.5 for NADH
  • Theoretical maximum of ~1.5 for FADH2
• Chemiosmotic coupling links electron transport and ATP synthesis processes
• Coupling ensures efficient energy conversion in mitochondria

Regulation of Electron Transport and Phosphorylation

Metabolic Regulators

• ADP availability primarily regulates oxidative phosphorylation
  • ATP synthesis slows when ADP levels are low (respiratory control)
• NAD+/NADH ratio influences electron transport rate
  • Higher ratio promotes faster electron flow through ETC
• Oxygen concentration affects electron transport rate
  • Oxygen serves as final electron acceptor in ETC

Allosteric and Feedback Regulation

• Allosteric regulation of ETC complexes modulates electron transport rates
  • ATP and other metabolites can regulate Complex IV
• Proton gradient acts as regulatory factor
  • High gradient slows electron transport (feedback inhibition)
• Calcium levels in mitochondrial matrix stimulate oxidative phosphorylation
  • Activates key enzymes in citric acid cycle and ETC
• Post-translational modifications alter ETC complex activity and efficiency
  • Phosphorylation of complexes can change their function

Proton Gradient and ATP Synthesis

Chemiosmotic Theory

• Peter Mitchell proposed chemiosmotic theory to explain ATP synthesis driven by proton gradient
• Proton gradient consists of two components
  • pH difference (ΔpH) across inner mitochondrial membrane
  • Electrical potential difference (Δψ) across inner mitochondrial membrane
• Proton-motive force (PMF) sums chemical and electrical gradient components
  • Typically 200-220 mV in actively respiring mitochondria

Energy Conversion and Mitochondrial Functions

• PMF provides thermodynamic driving force for ATP synthesis
  • Overcomes large positive Gibbs free energy required for ATP formation
• Tight coupling between electron transport and proton pumping ensures efficient energy conservation
• Proton gradient drives other mitochondrial processes
  • Import of proteins into mitochondrial matrix
  • Import of metabolites into mitochondrial matrix
• Maintaining proton gradient crucial for mitochondrial function and cellular energy homeostasis

Inhibitors and Uncouplers of Electron Transport vs Phosphorylation

Specific Inhibitors

• Rotenone inhibits Complex I
• Antimycin A blocks Complex III
• Cyanide and carbon monoxide inhibit Complex IV
  • Prevent oxygen reduction and halt electron transport
• Oligomycin inhibits ATP synthase
  • Blocks proton flow through enzyme
  • Stops ATP production while maintaining proton gradient

Uncouplers and Their Effects

• Uncouplers dissipate proton gradient without ATP synthesis
  • 2,4-dinitrophenol (DNP)
  • Carbonyl cyanide m-chlorophenyl hydrazone (CCCP)
• Uncoupling proteins (UCPs) in inner mitochondrial membrane physiologically uncouple electron transport from ATP synthesis
  • Generate heat instead of ATP

Applications and Significance

• Inhibitors and uncouplers crucial in elucidating electron transport and oxidative phosphorylation mechanisms
• Some inhibitors and uncouplers have therapeutic applications
  • Treatment of obesity (uncouplers)
  • Potential cancer therapies (ETC inhibitors)
• Others serve as environmental toxins or potential weapons
  • Rotenone used as pesticide
  • Cyanide as a potent poison