Electron Transport Chain (Complexes I–IV)

1. 1

   NADH + H+ + ubiquinone (Q) → NAD+ + ubiquinol (QH2)

   Complex I (NADH:ubiquinone oxidoreductase) 7.1.1.2 ST-0277 Irreversible/directional NAD+ NADH FMN Fe-S cluster Ubiquinone (CoQ)
   In NADH H+ Ubiquinone (CoQ)

   Out NAD+ Ubiquinol (CoQH2)
   › Notes

   Required cofactors: FMN, Fe–S clusters, NADH, and ubiquinone. For each NADH oxidized and Q reduced, Complex I translocates 4 H+ from matrix to intermembrane space; this electron-entry step is not normally called the committed rate-limiting step of oxidative phosphorylation, but it is a major regulated redox entry point.

2. 2

   Succinate + Q → fumarate + QH2

   Complex II (succinate dehydrogenase) 1.3.5.1 ST-0278 Irreversible/directional FAD Fe-S cluster Heme/cytochrome Ubiquinone (CoQ)
   In Succinate

   Out Fumarate Ubiquinol (CoQH2)
   › Notes

   Required cofactors: enzyme-bound FAD, Fe–S centers, heme b, and ubiquinone. Complex II pumps 0 H+; because FADH2-derived electrons enter at the Q pool and bypass Complex I, they yield less ATP than NADH-derived electrons. Other mitochondrial flavoproteins, including glycerol-3-phosphate dehydrogenase and electron-transfer flavoprotein:ubiquinone oxidoreductase, also feed electrons to Q.

3. 3

   QH2 + 2 cytochrome c(Fe3+) + 2 H+matrix → Q + 2 cytochrome c(Fe2+) + 4 H+intermembrane space

   Complex III (ubiquinol:cytochrome c oxidoreductase; cytochrome bc1) 7.1.1.8 ST-0279 Irreversible/directional Fe2+ Fe-S cluster Heme/cytochrome
   In Ubiquinol (CoQH2) Cytochrome c(Fe3+) H+ (matrix)

   Out Cytochrome c(Fe2+) H+ (intermembrane space)
   › Notes

   Required cofactors: cytochromes bL and bH, cytochrome c1, and the Rieske [2Fe–2S] protein. Through the Q cycle, oxidation of two QH2 molecules transfers two electrons to two cytochrome c molecules and results in a net 4 H+ translocated/released to the intermembrane space per electron pair; this is a key proton-pumping step.

4. 4

   2 cytochrome c(Fe2+) + 1/2 O2 + 2 H+matrix → 2 cytochrome c(Fe3+) + H2O

   Complex IV (cytochrome c oxidase) 7.1.1.9 ST-0280 Irreversible/directional Fe2+ Cu Heme/cytochrome O2 H2O
   In Cytochrome c(Fe2+) O2 H+ (matrix)

   Out Cytochrome c(Fe3+) H2O
   › Notes

   Required cofactors: CuA center, hemes a and a3, CuB, cytochrome c, O2, and matrix protons. Per pair of electrons (one NADH equivalent), Complex IV pumps 2 H+ from matrix to intermembrane space and also consumes 2 matrix H+ chemically to form water; for four electrons/O2 it pumps 4 H+ and consumes 4 matrix H+.

5. 5

   Electron-carrier integration: NADH/FADH2 → Q pool → Complex III → cytochrome c → Complex IV → O2

   ↪ Q pool → Complex III → cytochrome c → Complex IV → O2

   Mobile carriers: ubiquinone (CoQ) and cytochrome c ST-0281 Irreversible/directional NADH FADH2 Heme/cytochrome O2
   In NADH/FADH2

   Out Ubiquinone (CoQ)
   › Notes

   Cytochrome c is a small, soluble peripheral protein on the outer face of the inner membrane that carries one electron at a time from Complex III to Complex IV. For NADH-derived electrons, the ETC pumps a total of 10 H+ per NADH (4 at I, 4 at III, 2 at IV); for FADH2-derived electrons entering through Complex II, it pumps 6 H+ (0 at II, 4 at III, 2 at IV).

Showing all 5 steps.

Overview

The mitochondrial electron transport chain (ETC) transfers electrons from NADH and FADH2 to molecular oxygen through a sequence of redox carriers while using the released free energy to pump protons across the inner mitochondrial membrane. Electron flow establishes the proton-motive force that powers ATP synthesis, metabolite transport, and other mitochondrial work. Oxygen is the terminal electron acceptor; reduction of O2 to water prevents the respiratory chain from remaining in a reduced, electron-blocked state.

Cellular location

Complexes I–IV, ubiquinone, cytochrome c, and associated supercomplexes reside in the inner mitochondrial membrane. Complexes I, III, and IV pump protons from the matrix into the intermembrane space; the outer membrane is relatively permeable to small solutes, so the intermembrane-space environment communicates substantially with the cytosol. Aerobic tissues with high ATP demand—especially cardiac muscle, brain, renal cortex, liver, and oxidative skeletal muscle—depend heavily on ETC function; erythrocytes lack the organelle and respiratory chain.

Net energetics

The ETC itself produces no ATP directly; it converts redox energy into proton-motive force. Oxidation of one matrix NADH by the sequence I → III → IV pumps approximately 10 H+, whereas one FADH2-equivalent entering via Complex II → III → IV pumps approximately 6 H+. These proton-pumping stoichiometries underlie modern average P/O ratios of about 2.5 ATP per NADH and 1.5 ATP per FADH2 after accounting for ATP synthase and transport costs. Therefore, oxidation of the NADH and FADH2 generated from complete aerobic oxidation of glucose supports the conventional modern total of approximately 30–32 ATP per glucose, not the older approximate estimate of 36–38 ATP.

Clinical significance

The ETC is the main source of ATP in most aerobic tissues and is also a significant potential source of reactive oxygen species (ROS), particularly at Complexes I and III when electron carriers are highly reduced. Cyanide, carbon monoxide, azide, and hydrogen sulfide inhibit Complex IV, blocking oxygen utilization and causing rapidly fatal histotoxic hypoxia despite potentially normal arterial oxygen content. Pathogenic mitochondrial DNA or nuclear-gene variants affecting ETC subunits can cause heterogeneous mitochondrial diseases, often involving high-energy organs such as brain, skeletal muscle, heart, retina, and cochlea. Release of cytochrome c from damaged mitochondria also participates in intrinsic apoptotic signaling.