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ETC

ETC

5 min read Updated Apr 18, 2026

The electron transport chain (ETC) is where the NADH and FADH2 produced by glycolysis, PDH, the TCA cycle, and beta-oxidation finally cash in. The ETC is a series of protein complexes embedded in the inner mitochondrial membrane. NADH donates electrons at Complex I; FADH2 donates at Complex II. The electrons pass through the complexes, releasing energy used to pump protons from the matrix to the intermembrane space. Oxygen accepts the electrons at the end, forming water.

Put simply: the upstream pathways exist to produce NADH and FADH2 for the ETC. The ETC exists to build the proton gradient. ATP synthase (next section) uses the proton gradient to make ATP. Three linked machines, one goal.

The electron transport chain and chemiosmosis

Pathway map
Intermembrane space · protons pile up here Matrix I II III IV F₁ ATP synthase Q coenzyme Q c cytochrome c NADH glycolysis, PDH, TCA, β-oxidation FADH₂ succinate, β-oxidation ½ O₂ → H₂O the final acceptor no O₂, no flow, no ATP 4 H⁺ 4 H⁺ 2 H⁺ H⁺ falls back down the gradient it just climbed ADP + Pi → ATP rotenone antimycin A cyanide · CO oligomycin Blocked by I NADH dehydrogenase · II succinate dehydrogenase · III cytochrome bc₁ · IV cytochrome c oxidase Complex II pumps no protons, so FADH₂ is worth less than NADH Exchange rate 1 NADH ≈ 2.5 ATP 1 FADH₂ ≈ 1.5 ATP ATP synthase needs about 4 H⁺ per ATP
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Electron path Proton (H⁺) path Inner membrane Where inhibitors bind

Where the electrons come fromEvery NADH and FADH₂ made in glycolysis, PDH, the TCA cycle, and β-oxidation ends up here. This is the only place their energy becomes ATP, which is why every pathway upstream stalls the moment oxygen runs out.

Why FADH₂ is worth lessFADH₂ hands its electrons to coenzyme Q, skipping Complex I. Four fewer protons are pumped per pair of electrons, so FADH₂ yields about 1.5 ATP against NADH's 2.5.

Inhibitors vs uncouplersInhibitors stop electron flow, so the gradient collapses, ATP synthesis stops, and O₂ consumption stops with it. Uncouplers (2,4-DNP, thermogenin in brown fat) let protons leak back without passing through ATP synthase: electrons keep flowing and O₂ is still consumed, but the energy comes out as heat instead of ATP.

Electrons go across, protons go around. Complexes I, III, and IV use the energy of electron transfer to push protons into the intermembrane space; ATP synthase lets them fall back into the matrix and captures the energy as ATP. Complex II is the only complex that pumps nothing, which is the whole reason FADH₂ is worth less than NADH.

The Four Complexes

| Complex | Role | Proton pumping |
|---------|------|---------------|
| I (NADH dehydrogenase) | Accepts electrons from NADH; transfers to CoQ | Pumps 4 H+ |
| II (Succinate dehydrogenase) | Accepts electrons from FADH2 (succinate); transfers to CoQ | Does NOT pump protons |
| III (Cytochrome bc1) | Transfers electrons from CoQ to cytochrome c | Pumps 4 H+ |
| IV (Cytochrome c oxidase) | Transfers electrons from cytochrome c to O2, forming water | Pumps 2 H+ |

Mobile carriers:

  • CoQ (ubiquinone): lipid-soluble carrier that shuttles electrons from I and II to III within the membrane.
  • Cytochrome c: small peripheral protein that shuttles electrons from III to IV in the intermembrane space.

Why NADH > FADH2 in ATP Yield

NADH enters at Complex I. Complex I + III + IV all pump protons = 10 H+ total per NADH. FADH2 enters at Complex II (which does not pump), so only Complexes III and IV pump = 6 H+ total per FADH2. Fewer protons pumped means less ATP made.

Standard approximations:

  • Per NADH: ~2.5 ATP.
  • Per FADH2: ~1.5 ATP.

Final Electron Acceptor

Oxygen at Complex IV. Four electrons + 4 H+ + O2 → 2 H2O. Without oxygen, electrons cannot leave the chain, and the entire chain backs up. NADH cannot be recycled back to NAD+, so the TCA cycle and pyruvate dehydrogenase stop. Only glycolysis can continue (anaerobically), relying on lactate fermentation to recycle NAD+.

Oxidative stress: the cost of breathing

Pathway map
Inner mitochondrial membrane Complexes I and III leak about 1 to 2 percent of their electrons straight onto O₂ instead of passing them along the chain. Complex I Complex II Complex III Complex IV ATP synthase Superoxide O₂•⁻ superoxide dismutase Mn in matrix · Cu-Zn in cytosol H₂O₂ catalase in the peroxisome H₂O + O₂ glutathione peroxidase spends two reduced glutathione 2 H₂O 2 GSH GSSG glutathione reductase needs NADPH FROM THE PENTOSE PHOSPHATE PATHWAY the only way to reset glutathione Fe²⁺ · Fenton Hydroxyl radical •OH Nothing defuses this one. It reacts with whatever it touches first: lipid peroxidation in membranes strand breaks in DNA carbonyl damage to proteins Mitochondrial DNA sits closest to the leak and has no histones, so it takes the worst of it. When the damage wins, the mitochondrion starts the cell's own demolition Damaged mitochondrion Cytochrome c out Apoptosome Caspase 3 Apoptosis plus caspase 9 BCL-2 holds the membrane shut BAX opens it. Too much BCL-2 and the cell refuses to die, which is how it acts as an oncogene. G6PD deficiency. A red cell has no mitochondria and no nucleus, so the pentose phosphate pathway is its only NADPH source. Without it glutathione cannot be reset, so fava beans, sulfa drugs, or an infection denature hemoglobin into Heinz bodies: bite cells and hemolysis.
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Inner mitochondrial membrane Damaging species The enzymes that defuse it NADPH, from the pentose phosphate pathway

Why the pentose phosphate pathway matters hereGlutathione is the cell's reusable antioxidant, but it only works in its reduced form. Glutathione reductase resets it and the reducing power comes from NADPH, which for most cells means the pentose phosphate pathway. That is the whole reason a pathway that makes no ATP is still essential.

G6PD deficiency in one lineA red blood cell has no mitochondria and no nucleus, so the pentose phosphate pathway is its only source of NADPH. Lose glucose-6-phosphate dehydrogenase and glutathione cannot be reset, so an oxidative challenge (fava beans, sulfa drugs, infection) denatures hemoglobin into Heinz bodies, and the spleen bites them out, leaving bite cells and hemolysis.

The same organelle kills the cellCytochrome c is a normal carrier between complexes III and IV. If the mitochondrion is damaged badly enough it leaks into the cytosol, where it assembles the apoptosome and activates caspase 9 and then caspase 3. BCL-2 holds the membrane shut and BAX opens it, which is why BCL-2 behaves as an oncogene when overexpressed: the cell simply refuses to die.

Oxygen is a superb electron acceptor and a dangerous one. A small fraction of electrons escape complexes I and III early and make superoxide. Everything on the top row exists to defuse that, everything on the left is what happens when it is not defused, and the bottom row is the cell's decision to give up.
Why does NADH yield more ATP than FADH2 per electron pair?
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NADH enters the ETC at Complex I, so electrons pass through I, III, and IV - three proton-pumping complexes. FADH2 enters at Complex II (succinate dehydrogenase), which does not pump protons. FADH2 electrons therefore only pass through III and IV. Fewer protons pumped means less ATP made per FADH2 (~1.5) compared to NADH (~2.5).
What is the role of oxygen in the electron transport chain?
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Oxygen is the final electron acceptor at Complex IV. Four electrons combine with O2 and 4 H+ to form 2 water molecules. Without oxygen, electrons cannot leave the chain, all the carriers become reduced, NADH cannot be recycled back to NAD+, and the TCA cycle halts. The entire aerobic energy system depends on O2 accepting electrons at the end.
What do CoQ and cytochrome c do in the ETC?
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Both are mobile electron carriers. CoQ (ubiquinone) is lipid-soluble and shuttles electrons from Complex I and Complex II to Complex III within the membrane. Cytochrome c is a peripheral membrane protein in the intermembrane space that shuttles electrons from Complex III to Complex IV. Without these carriers, the large complexes could not pass electrons between themselves.
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