Proton-Translocating NADH-Ubiquinone Oxidoreductase: Interaction with Artificial Electron Acceptors, Inhibitors, and...

Proton-translocating NADH-ubiquinone oxidoreductase (complex I) catalyzes the oxidation of NADH by ubiquinone accompanied by the transmembrane transfer of four protons, thus contributing to the formation of a proton motive force (pmf) across the coupling membranes of mitochondria and bacteria, which drives ATP synthesis in oxidative phosphorylation. In recent years, great progress has been achieved in resolving complex I structure by means of X-ray crystallography and high-resolution cryo-electron microscopy, which has led to the formulation of detailed hypotheses concerning the molecular mechanism of coupling of the redox reaction to vectorial proton translocation. To test and probe proposed mechanisms, a comprehensive study of complex I using other methods including molecular dynamics and a variety of biochemical studies such as kinetic and inhibitory analysis is required. Due to complex I being a major electron entry point for oxidative metabolism, various mutations of the enzyme lead to the development of severe pathologies and/or are associated with human metabolic disorders and have been well documented. This review examines current information on the structure and subunit composition of complex I of eukaryotes and prokaryotes, reactions catalyzed by this enzyme, and ways to regulate them. The review also discusses biomedical aspects related to the enzyme in light of recent findings.