The mitochondrial-encoded subunits of respiratory complex I (NADH:ubiquinone oxidoreductase): identifying residues important in mechanism and disease.

TitleThe mitochondrial-encoded subunits of respiratory complex I (NADH:ubiquinone oxidoreductase): identifying residues important in mechanism and disease.
Publication TypeJournal Article
Year of Publication2011
AuthorsBridges, HR, Birrell, JA, Hirst, J
JournalBiochem Soc Trans
Volume39
Issue3
Pagination799-806
Date Published2011 Jun
ISSN1470-8752
KeywordsAmino Acid Sequence, Animals, Disease, Electron Transport Complex I, Humans, Mitochondria, Models, Molecular, Mutagenesis, Site-Directed, Mutation, NAD, Oxidation-Reduction, Protein Structure, Secondary, Protein Structure, Tertiary, Protein Subunits
Abstract

Complex I (NADH:ubiquinone oxidoreductase) is crucial to respiration in many aerobic organisms. The hydrophilic domain of complex I, containing nine or more redox cofactors, and comprising seven conserved core subunits, protrudes into the mitochondrial matrix or bacterial cytoplasm. The α-helical membrane-bound hydrophobic domain contains a further seven core subunits that are mitochondrial-encoded in eukaryotes and named the ND subunits (ND1-ND6 and ND4L). Complex I couples the oxidation of NADH in the hydrophilic domain to ubiquinone reduction and proton translocation in the hydrophobic domain. Although the mechanisms of NADH oxidation and intramolecular electron transfer are increasingly well understood, the mechanisms of ubiquinone reduction and proton translocation remain only poorly defined. Recently, an α-helical model of the hydrophobic domain of bacterial complex I [Efremov, Baradaran and Sazanov (2010) Nature 465, 441-447] revealed how the 63 transmembrane helices of the seven core subunits are arranged, and thus laid a foundation for the interpretation of functional data and the formulation of mechanistic proposals. In the present paper, we aim to correlate information from sequence analyses, site-directed mutagenesis studies and mutations that have been linked to human diseases, with information from the recent structural model. Thus we aim to identify and discuss residues in the ND subunits of mammalian complex I which are important in catalysis and for maintaining the enzyme's structural and functional integrity.

DOI10.1042/BST0390799
Alternate JournalBiochem. Soc. Trans.
Citation Key10.1042/BST0390799
PubMed ID21599651
Grant ListMC_U105663141 / / Medical Research Council / United Kingdom