What is the electron transport chain and where does it work?
The electron transport chain (ETC) is a series of protein complexes and mobile carriers in the inner mitochondrial membrane. Electrons from NADH and FADH2, made in glycolysis, the link reaction, beta-oxidation and the citric acid cycle, pass through carriers of increasing reduction potential until they reach oxygen, the final acceptor, forming water. The energy released pumps protons (H+) from the matrix into the intermembrane space.
Oxidative phosphorylation has two linked parts: the ETC builds the proton gradient, and chemiosmosis lets protons flow back through ATP synthase, which makes ATP. The gradient — the proton-motive force — is the link between the two. This is the chemiosmotic principle in one line: electron flow and ATP synthesis are coupled only through the gradient, which is why agents that let protons leak back 'uncouple' them.
- Order of carriers: complex I → (complex II as a second entry) → coenzyme Q → complex III → cytochrome c → complex IV → O2.
- Mobile carriers: coenzyme Q (ubiquinone, with a hydrophobic tail that keeps it in the membrane) and cytochrome c, a small haem protein that carries one electron at a time.
- Proton pumps: complexes I, III and IV. Complex II pumps none.
What does each complex of the electron transport chain do?
| Complex | Name | Key components | Electrons from → to | H+ pumped |
|---|---|---|---|---|
| I | NADH dehydrogenase (NADH–ubiquinone oxidoreductase) | FMN, Fe–S clusters | NADH → coenzyme Q | 4 |
| II | Succinate dehydrogenase (also a citric acid cycle enzyme) | FAD, Fe–S clusters | Succinate (via FADH2) → coenzyme Q | 0 |
| CoQ | Ubiquinone | Quinone with hydrophobic tail | Complexes I and II → complex III | — |
| III | Cytochrome c reductase (cytochrome bc1) | Cytochrome b, Rieske Fe–S, cytochrome c1; Q cycle | CoQH2 → cytochrome c | 4 |
| IV | Cytochrome c oxidase | Cytochromes a and a3, haem and copper centres | Cytochrome c → O2 (forms water) | 2 |
| V | ATP synthase | F0 (membrane proton channel) and F1 (catalytic head in the matrix) | Uses H+ flowing back into the matrix | About 4 H+ per ATP |
Other enzymes also feed electrons to coenzyme Q: glycerol-3-phosphate dehydrogenase (the shuttle that carries electrons of cytosolic NADH) and acyl-CoA dehydrogenase (the first step of beta-oxidation, producing FADH2). Complex III cannot hand two electrons to cytochrome c at once — cytochrome c takes one electron at a time — so it runs the two-step Q cycle.
How does ATP synthase turn the proton gradient into ATP?
ATP synthase (complex V) has two parts. F0 is hydrophobic and sits in the inner membrane; it contains a proton channel that is protonated and deprotonated as H+ flows down its gradient from the intermembrane space into the matrix. That alternating charge makes F0 rotate. F1 is hydrophilic and faces the matrix; the rotation changes the shape of its subunits, and those conformational changes join ADP and Pi into ATP — a rotary motor, often compared to a turbine.
The gradient has two parts: a chemical part (the intermembrane space is more acidic) and an electrical part (positive outside, negative inside). Together they form the proton-motive force. Anything that dissipates this force — a leaky membrane, an uncoupling protein or a drug that carries protons — stops ATP synthesis even if electrons keep flowing.
Which drugs and poisons inhibit each complex?
| Site | Inhibitor | Notes for exams |
|---|---|---|
| Complex I | Rotenone; some barbiturates | Rotenone is a pesticide and fish poison; it blocks transfer from Fe–S clusters to ubiquinone |
| Complex II | Carboxin | Fungicide that blocks the ubiquinone-binding site |
| Coenzyme Q | Doxorubicin (proposed) | Interference with CoQ is one proposed mechanism of doxorubicin cardiomyopathy |
| Complex III | Antimycin A | Binds the Qi site of cytochrome c reductase, stopping the Q cycle |
| Complex IV | Cyanide, carbon monoxide, azide (and hydrogen sulphide) | Block cytochrome c oxidase — cells cannot use oxygen |
| Complex V | Oligomycin | Macrolide from Streptomyces; blocks the F0 proton channel of ATP synthase |
Inhibitors stop electron flow, so oxygen is not reduced and ATP formation stops. In cyanide poisoning the tissues cannot extract oxygen, so venous blood stays oxygen-rich ('arterialisation' of venous blood) and the hypoxia does not respond to supplemental oxygen. Cells switch to anaerobic glycolysis, producing lactic acidosis: a serum lactate of 8 mmol/L or more is described as both sensitive and specific for toxic cyanide levels in suspected exposure.
How do cyanide and carbon monoxide poisoning differ?
| Feature | Cyanide | Carbon monoxide |
|---|---|---|
| Target | Cytochrome c oxidase (complex IV) | Cytochrome c oxidase and haemoglobin (carboxyhaemoglobin) |
| Typical sources | House fires (burning furniture, rugs), jewellery cleaners, plastic manufacture, nitroprusside, apricot/peach/apple seeds | House fires, vehicle exhaust, wood or gas stoves, paint strippers |
| Clue | Almond breath odour; hypoxia unresponsive to oxygen; high lactate | Pulse oximeter may read normal — use a co-oximeter |
| Antidote | Hydroxocobalamin (forms cyanocobalamin); or nitrites (make methaemoglobin) with thiosulfate | Oxygen to displace CO |
For a broader look at why cyanide, CO, metformin and iron cause a high anion gap acidosis, see the anion gap page; the same cyanide and CO pair sits at the start of the 'CAT MUDPILES' mnemonic.
How do uncouplers like 2,4-DNP and thermogenin work?
An uncoupler lets protons leak back into the matrix without passing through ATP synthase. The gradient collapses, so ATP is not made, but electron flow continues — in fact the chain works harder, oxygen use rises and the energy is released as heat. Cells fall back on anaerobic metabolism, which can cause a type B lactic acidosis.
| Feature | ETC inhibitor (e.g. cyanide) | Uncoupler (e.g. 2,4-DNP) |
|---|---|---|
| Electron flow | Stops | Continues — even speeds up |
| ATP synthesis | Stops | Stops |
| Oxygen use | Falls | Rises |
| Heat | No increase | Hyperthermia |
- 2,4-Dinitrophenol (DNP): sold over the internet as a slimming aid; it uncouples oxidative phosphorylation and causes hyperthermia, tachycardia, sweating and tachypnoea, which can be fatal.
- Salicylates (aspirin): uncouple oxidative phosphorylation; overdose classically causes tinnitus and early respiratory alkalosis, followed by a mixed respiratory alkalosis and metabolic acidosis.
- Thermogenin (UCP1): a physiological uncoupler — a proton channel in the mitochondria of brown adipose tissue that generates heat without shivering. Brown fat is abundant in newborns and hibernating animals.
What are the P:O ratios for NADH and FADH2?
The P:O ratio is the number of ATP made per oxygen atom reduced — that is, per pair of electrons passed to oxygen. It follows from the proton arithmetic: NADH pumps 10 H+ (4 + 4 + 2) and ATP synthase needs about 4 H+ per ATP, so NADH gives about 2.5 ATP. FADH2 enters at complex II, bypassing the first pump, moves 6 H+ and gives about 1.5 ATP.
P:O (NADH) ≈ 10 H⁺ ÷ 4 H⁺ per ATP ≈ 2.5; P:O (FADH₂) ≈ 6 ÷ 4 ≈ 1.5
Older textbooks round these to 3 and 2. Choose the modern values (2.5 and 1.5) unless the options only offer the older ones.
Which clinical conditions involve the electron transport chain?
- MELAS (mitochondrial encephalopathy, lactic acidosis and stroke-like episodes) — a mitochondrial DNA disorder affecting oxidative phosphorylation, with weakness and seizures from childhood.
- Cyanide toxicity — from fires, nitroprusside infusion or cyanogenic seeds; treated with hydroxocobalamin.
- Carbon monoxide poisoning — complex IV block plus carboxyhaemoglobin; treated with oxygen.
- Salicylate and DNP overdose — uncoupling with hyperthermia and acid–base disturbance.
- Doxorubicin cardiomyopathy — one proposed mechanism is reactive oxygen species from disturbed electron transfer at coenzyme Q.
- Neonatal heat production — non-shivering thermogenesis by thermogenin in brown fat.