Atomic structure of the entire mammalian mitochondrial complex i Journal Article

Author(s): Fiedorczuk, Karol; Letts, James A; Degliesposti, Gianluca; Kaszuba, Karol; Skehel, Mark; Sazanov, Leonid A
Article Title: Atomic structure of the entire mammalian mitochondrial complex i
Affiliation IST Austria
Abstract: Mitochondrial complex I (also known as NADH:ubiquinone oxidoreductase) contributes to cellular energy production by transferring electrons from NADH to ubiquinone coupled to proton translocation across the membrane. It is the largest protein assembly of the respiratory chain with a total mass of 970 kilodaltons. Here we present a nearly complete atomic structure of ovine (Ovis aries) mitochondrial complex I at 3.9 Å resolution, solved by cryo-electron microscopy with cross-linking and mass-spectrometry mapping experiments. All 14 conserved core subunits and 31 mitochondria-specific supernumerary subunits are resolved within the L-shaped molecule. The hydrophilic matrix arm comprises flavin mononucleotide and 8 iron-sulfur clusters involved in electron transfer, and the membrane arm contains 78 transmembrane helices, mostly contributed by antiporter-like subunits involved in proton translocation. Supernumerary subunits form an interlinked, stabilizing shell around the conserved core. Tightly bound lipids (including cardiolipins) further stabilize interactions between the hydrophobic subunits. Subunits with possible regulatory roles contain additional cofactors, NADPH and two phosphopantetheine molecules, which are shown to be involved in inter-subunit interactions. We observe two different conformations of the complex, which may be related to the conformationally driven coupling mechanism and to the active-deactive transition of the enzyme. Our structure provides insight into the mechanism, assembly, maturation and dysfunction of mitochondrial complex I, and allows detailed molecular analysis of disease-causing mutations.
Keywords: Mammalia; Ovis; Ovis aries
Journal Title: Nature
Volume: 538
Issue 7625
ISSN: 0028-0836
Publisher: Nature Publishing Group  
Date Published: 2016-01-01
Start Page: 406
End Page: 410
DOI: 10.1038/nature19794
Notes: We thank the ETH Zurich ScopeM Center for access to Titan Krios EM. Data processing was performed at the IST high-performance computer cluster. K.F. is partially funded by the Medical Research Council UK PhD fellowship. J.A.L. holds a long-term fellowship from FEBS. This project has received funding from the European Union’s 2020 research and innovation programme under grant agreement No 701309.
Open access: no