Electron Transport Chain & Oxidative Phosphorylation

The electron transport chain is a series of protein complexes in the inner mitochondrial membrane that passes electrons from NADH and FADH2 to oxygen, pumping protons across the membrane as it goes. Oxidative phosphorylation is the second act: the enzyme ATP synthase lets those protons flow back and uses their energy to make ATP from ADP.

This is the cell's main power station - the reason we breathe oxygen at all. One glucose molecule yields about 30 ATP through this system, compared with just 2 from glycolysis alone. Poisons like cyanide kill in minutes precisely because they jam this chain, and mitochondrial defects cause diseases of energy-hungry tissues like muscle and brain.

Key Concepts

• Complex I (NADH dehydrogenase): accepts electrons from NADH, pumps 4 protons.
• Complex II (succinate dehydrogenase): accepts electrons from FADH2, pumps no protons.
• Coenzyme Q and cytochrome c: mobile carriers shuttling electrons between complexes.
• Complexes III and IV: pump protons; complex IV hands the electrons to oxygen, the final acceptor, forming water.
• Chemiosmotic theory (Peter Mitchell): the proton gradient itself is the energy store that ATP synthase taps.
• ATP synthase (complex V): a rotary motor making 3 ATP per full turn as protons stream through.
• P/O ratio: about 2.5 ATP per NADH and 1.5 per FADH2 with modern measurements.
• Inhibitors: rotenone (complex I), antimycin A (complex III), cyanide and carbon monoxide (complex IV), oligomycin (ATP synthase); uncouplers like 2,4-DNP let protons leak back without making ATP, releasing heat.

Formulas

• Terminal reaction: NADH + H+ + 1/2 O2 --> NAD+ + H2O (drives the pumping of about 10 protons per NADH).
• ATP synthesis: ADP + Pi + energy --> ATP + H2O (catalysed by ATP synthase).
• Glucose total: 2 (glycolysis net) + 2x1.5 (cytosolic NADH) + 2x2.5 (pyruvate dehydrogenase NADH) + 6x2.5 (Krebs NADH) + 2x1.5 (FADH2) + 2 (GTP) = about 30 ATP; with the malate-aspartate shuttle it is 32.
• Assumes the glycerol-phosphate shuttle for cytosolic NADH; heart and liver use the malate-aspartate shuttle instead.

Worked Example

Count the ATP from one glucose with the glycerol-phosphate shuttle. Glycolysis: net 2 ATP + 2 cytosolic NADH x 1.5 = 3. Pyruvate dehydrogenase: 2 NADH x 2.5 = 5. Krebs cycle: 6 NADH x 2.5 = 15, plus 2 FADH2 x 1.5 = 3, plus 2 GTP = 2. Total = 2 + 3 + 5 + 15 + 3 + 2 = 30 ATP, replacing the older 36-38 figure based on outdated P/O ratios.

Common Misconceptions

• Oxygen is used in the Krebs cycle. It is not - the Krebs cycle only makes NADH and FADH2; oxygen waits at the end of the electron transport chain as the final electron acceptor.
• The chain makes ATP directly. The chain only builds the proton gradient; ATP synthase makes the ATP, which is why oligomycin stops ATP synthesis while electron flow can continue briefly.
• 36 ATP per glucose is the exact modern figure. Modern P/O measurements give about 30-32; the 36-38 figure is outdated.

Real-World Applications

• Cyanide poisoning is treated by restoring complex IV function (nitrites, thiosulfate, hydroxocobalamin).
• Mitochondrial diseases (MELAS, Leigh syndrome) are diagnosed through this biochemistry.
• Brown fat burns calories by uncoupling the gradient to make heat, a target in obesity research.
• Exercise physiology: endurance training increases mitochondrial density and oxidative capacity.

Electrons fall from NADH to oxygen, protons pile up outside the inner membrane, and ATP synthase cashes in the gradient as ATP - about 30 per glucose. Block the chain and the cell starves in minutes; that is why oxygen, cyanide, and mitochondria all meet in this one pathway.