Letter | Published:

Structure of mammalian respiratory complex I

Nature volume 536, pages 354358 (18 August 2016) | Download Citation

Abstract

Complex I (NADH:ubiquinone oxidoreductase), one of the largest membrane-bound enzymes in the cell, powers ATP synthesis in mammalian mitochondria by using the reducing potential of NADH to drive protons across the inner mitochondrial membrane. Mammalian complex I (ref. 1) contains 45 subunits, comprising 14 core subunits that house the catalytic machinery (and are conserved from bacteria to humans) and a mammalian-specific cohort of 31 supernumerary subunits1,2. Knowledge of the structures and functions of the supernumerary subunits is fragmentary. Here we describe a 4.2-Å resolution single-particle electron cryomicroscopy structure of complex I from Bos taurus. We have located and modelled all 45 subunits, including the 31 supernumerary subunits, to provide the entire structure of the mammalian complex. Computational sorting of the particles identified different structural classes, related by subtle domain movements, which reveal conformationally dynamic regions and match biochemical descriptions of the ‘active-to-de-active’ enzyme transition that occurs during hypoxia3,4. Our structures therefore provide a foundation for understanding complex I assembly5 and the effects of mutations that cause clinically relevant complex I dysfunctions6, give insights into the structural and functional roles of the supernumerary subunits and reveal new information on the mechanism and regulation of catalysis.

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Accessions

Primary accessions

Electron Microscopy Data Bank

Data deposits

The electron microscopy maps and models for each class have been deposited in the Electron Microscopy Data Bank (EMDB) with accession numbers EMD-4040 (class 1), EMD-4032 (class 2) and EMD-4041 (class 3), and in the Protein Data Bank with accessions 5LDW (class 1), 5LC5 (class 2) and 5LDX (class 3).

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Acknowledgements

We thank R. Henderson and G. Murshudov for discussions, J. Grimmett and T. Darling for computational help, S. Chen and C. Savva for electron microscopy help, and J. N. Blaza for quantifying the ratio of de-active and active enzymes in our preparation. This work was supported by The Medical Research Council, grant numbers U105184322 (K.R.V., in R. Henderson’s group) and U105663141 (J.H.).

Author information

Author notes

    • Jiapeng Zhu

    Present address: Nanjing University of Chinese Medicine, Nanjing 210023, China.

    • Jiapeng Zhu
    •  & Kutti R. Vinothkumar

    These authors contributed equally to this work.

Affiliations

  1. MRC Mitochondrial Biology Unit, Hills Road, Cambridge CB2 0XY, UK

    • Jiapeng Zhu
    •  & Judy Hirst
  2. MRC Laboratory of Molecular Biology, Francis Crick Avenue, Cambridge CB2 0QH, UK

    • Kutti R. Vinothkumar

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Contributions

J.Z. prepared protein; K.R.V. carried out electron microscopy data collection and analysis with help from J.Z.; J.Z. built the initial model; J.Z., K.R.V. and J.H. worked together, led by J.H., to model and analyse the data; J.H. designed the project; J.H. wrote the paper with help from J.Z. and K.R.V.

Competing interests

The authors declare no competing financial interests.

Corresponding authors

Correspondence to Kutti R. Vinothkumar or Judy Hirst.

Reviewer Information

Nature thanks R. B. Gennis, M. T. Ryan and the other anonymous reviewer(s) for their contribution to the peer review of this work.

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DOI

https://doi.org/10.1038/nature19095

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