title: Architecture of mammalian respiratory complex I.
abstract: Complex I (NADH:ubiquinone oxidoreductase) is essential for oxidative phosphorylation in mammalian mitochondria. It couples electron transfer from NADH to ubiquinone with proton translocation across the energy-transducing inner membrane, providing electrons for respiration and driving ATP synthesis. Mammalian complex I contains 44 different nuclear- and mitochondrial-encoded subunits, with a combined mass of 1 MDa. The 14 conserved 'core' subunits have been structurally defined in the minimal, bacterial complex, but the structures and arrangement of the 30 'supernumerary' subunits are unknown. Here we describe a 5 Å resolution structure of complex I from Bos taurus heart mitochondria, a close relative of the human enzyme, determined by single-particle electron cryo-microscopy. We present the structures of the mammalian core subunits that contain eight iron-sulphur clusters and 60 transmembrane helices, identify 18 supernumerary transmembrane helices, and assign and model 14 supernumerary subunits. Thus, we considerably advance knowledge of the structure of mammalian complex I and the architecture of its supernumerary ensemble around the core domains. Our structure provides insights into the roles of the supernumerary subunits in regulation, assembly and homeostasis, and a basis for understanding the effects of mutations that cause a diverse range of human diseases.
authors.affiliation: MRC Laboratory of Molecular Biology, Francis Crick Avenue, Cambridge, CB2 0QH, UK.
authors.forename: Kutti R
authors.initials: KR
authors.lastname: Vinothkumar
authors.affiliation: MRC Mitochondrial Biology Unit, Wellcome Trust / MRC Building, Hills Road, Cambridge, CB2 0XY, UK.
authors.forename: Jiapeng
authors.initials: J
authors.lastname: Zhu
authors.affiliation: MRC Mitochondrial Biology Unit, Wellcome Trust / MRC Building, Hills Road, Cambridge, CB2 0XY, UK.
authors.forename: Judy
authors.initials: J
authors.lastname: Hirst
mesh_terms: D000818:Animals; D002417:Cattle; D020285:Cryoelectron Microscopy; D042967:Electron Transport Complex I / Q000737:chemistry* / Q000648:ultrastructure*; D008929:Mitochondria, Heart / Q000201:enzymology; D008958:Models, Molecular; D017434:Protein Structure, Tertiary; D021122:Protein Subunits / Q000737:chemistry
chemical_list: D021122:Protein Subunits; D042967:Electron Transport Complex I