Electron transport chain (oxidative phosphorylation)

The electron transport chain (ETC) consists of four inner mitochondrial membrane protein complexes — Complex I (NADH:ubiquinone oxidoreductase), Complex II (succinate dehydrogenase), Complex III (cytochrome bc1), and Complex IV (cytochrome c oxidase) — that sequentially accept and donate electrons from NADH and FADH₂, coupling redox flow to proton pumping from the mitochondrial matrix into the intermembrane space. The resulting electrochemical gradient (proton-motive force) drives ATP synthase (Complex V) to phosphorylate ADP to ATP, a process termed oxidative phosphorylation (OXPHOS). A small fraction of electrons escape at Complexes I and III and react with oxygen to generate superoxide, the primary mitochondrial reactive oxygen species (ROS). With aging, activities of Complexes I and IV decline in human skeletal muscle and brain, accompanied by elevated ROS production, accumulating mitochondrial DNA (mtDNA) mutations, and reduced ATP output — all features of the mitochondrial dysfunction hallmark. The causal relationship is bidirectional: mtDNA damage impairs ETC subunit synthesis, and impaired ETC accelerates further mtDNA oxidative lesions. Partial pharmacological inhibition of Complex I (e.g., metformin) reduces reverse electron transfer-driven ROS and activates AMPK; whether this strategy extends healthspan in humans remains under investigation in trials such as TAME.