Chapter 3: Structure and Function of Respiratory Complex I

Proton-pumping NADH : ubiquinone oxidoreductase (respiratory complex I) is a very large and intricate membrane protein complex with a key role in aerobic energy metabolism. Complex I dysfunction causes a number of hereditary and degenerative disorders. The enzyme complex comprises fourteen central subunits that are conserved from bacteria to humans; some 30 additional accessory subunits are typically found in complex I from eukaryotes. The structure of complex I was determined by X-ray crystallography and electron microscopy. The central subunits can be assigned to functional modules for NADH oxidation, ubiquinone reduction, and proton pumping. Electron transfer and proton translocation are spatially separated and the ubiquinone reduction site is found in the hydrophilic peripheral arm of the enzyme complex. Functional studies, structure determination and computational approaches have tremendously advanced our understanding of redox-linked proton translocation by respiratory complex I. However, molecular details and even fundamental issues of the coupling mechanism remain unresolved or speculative. This review discusses the structural basis of current mechanistic models.