Abstract. Oxidative phosphorylation, i.e., ATP synthesis by the oxygen-consuming respiratory chain (RC), supplies most organs and tissues with a readily usable energy source, being functional before birth. Consequently, RC deficiencies can theoretically give rise to any symptom, in any organ or tissue, at any age and with any mode of inheritance, because of the twofold genetic origin of RC components (nuclear DNA and mitochondrial DNA). It was long wrongly considered that RC disorders originate from mutations of mitochondrial DNA, because for a long time only mutations or deletions of mitochondrial DNA were identified. However, the number of known disease-causing mutations in nuclear genes is steadily growing. These genes encode the various subunits of each complex, ancillary proteins functioning at different stages of holoenzyme biogenesis, including transcription, translation, chaperoning, addition of prosthetic groups, and protein assembly, and various enzymes involved in mitochondrial DNA metabolism.The mitochondrial respiratory chain (RC) catalyzes the oxidation of fuel molecules and the concomitant energy transduction into ATP via five complexes, which are embedded in the inner mitochondrial membrane (1) (Figure 1). Complex I [NADHcoenzyme Q (CoQ) reductase] carries reducing equivalents from NADH to CoQ (ubiquinone) and consists of Ͼ40 different polypeptides. Complex II (succinate-CoQ reductase) carries reducing equivalents from FADH 2 to CoQ and contains four polypeptides, including the FAD-dependent succinate dehydrogenase and iron-sulfur proteins. Complex III (reduced CoQ-cytochrome c reductase) carries electrons from CoQ to cytochrome c. It contains 11 subunits. Complex IV [cytochrome c oxidase (COX)], the terminal oxidase of the RC, catalyzes the transfer of reducing equivalents from cytochrome c to molecular oxygen. It is composed of two cytochromes (cytochromes a and a 3 ), two copper atoms, and 13 different protein subunits.During the oxidation process, electrons are transferred to oxygen via the energy-transducing complexes of the RC, i.e., complexes I, III, and IV for NADH-producing substrates; complexes II, III, and IV for succinate; and complexes III and IV for FADH 2 derived from the -oxidation pathway via the electron transfer flavoprotein and the electron transfer flavoprotein-CoQ oxidoreductase system. CoQ, a highly hydrophobic quinone, and cytochrome c, a low-molecular weight hemoprotein, act as "shuttles" between the complexes. The free energy generated from the redox reactions is converted into a transmembrane proton gradient. Protons are pumped through complexes I, III, and IV of the RC, which creates a charge differential. Complex V (ATP synthase) allows protons to flow back into the mitochondrial matrix and uses the released energy to synthesize ATP. Three ATP molecules are produced for each NADH molecule oxidized.