Electron transport chain (oxidative phosphorylation)

The electron transport chain (ETC) is a set of four protein complexes in your inner mitochondrial membrane. They are Complex I (NADH:ubiquinone oxidoreductase), Complex II (succinate dehydrogenase), Complex III (cytochrome bc1), and Complex IV (cytochrome c oxidase). They pass electrons down the line, from NADH and FADH₂, while pumping protons from the mitochondrial interior into the inter-membrane space. That builds an electrochemical gradient (a 'proton-motive force'). The gradient then drives ATP synthase (Complex V) to make ATP from ADP. The whole process is called oxidative phosphorylation (OXPHOS). A small fraction of electrons leak at Complexes I and III. They react with oxygen to form superoxide, the main mitochondrial reactive oxygen species (ROS). With age, the activity of Complexes I and IV declines in human muscle and brain. That comes with more ROS, accumulating mtDNA mutations, and less ATP, all features of the mitochondrial-dysfunction hallmark. The cause-and-effect runs both ways: mtDNA damage impairs the building of ETC parts, and a faulty ETC speeds further mtDNA damage. Partially inhibiting Complex I (as metformin does) reduces a particular kind of ROS and activates AMPK. Whether that extends human healthspan is being tested in trials like TAME.

Last reviewed: June 22, 2026

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