Structure of the Deactive State of Mammalian Respiratory Complex I

Structure. 2018 Feb 6;26(2):312-319.e3. doi: 10.1016/j.str.2017.12.014. Epub 2018 Jan 26.


Complex I (NADH:ubiquinone oxidoreductase) is central to energy metabolism in mammalian mitochondria. It couples NADH oxidation by ubiquinone to proton transport across the energy-conserving inner membrane, catalyzing respiration and driving ATP synthesis. In the absence of substrates, active complex I gradually enters a pronounced resting or deactive state. The active-deactive transition occurs during ischemia and is crucial for controlling how respiration recovers upon reperfusion. Here, we set a highly active preparation of Bos taurus complex I into the biochemically defined deactive state, and used single-particle electron cryomicroscopy to determine its structure to 4.1 Å resolution. We show that the deactive state arises when critical structural elements that form the ubiquinone-binding site become disordered, and we propose reactivation is induced when substrate binding to the NADH-reduced enzyme templates their reordering. Our structure both rationalizes biochemical data on the deactive state and offers new insights into its physiological and cellular roles.

Keywords: NADH:ubiquinone oxidoreductase; PEGylated gold grid; cryo-EM; disordered protein structure; electron transport chain; membrane protein; mitochondria.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cattle
  • Cryoelectron Microscopy
  • Electron Transport Complex I / metabolism*
  • Mitochondria / metabolism*
  • Models, Molecular*
  • Oxidation-Reduction
  • Ubiquinone / metabolism


  • Ubiquinone
  • Electron Transport Complex I