Mitochondrial complex I structure reveals ordered water molecules for catalysis and proton translocation

Nat Struct Mol Biol. 2020 Oct;27(10):892-900. doi: 10.1038/s41594-020-0473-x. Epub 2020 Aug 3.


Mitochondrial complex I powers ATP synthesis by oxidative phosphorylation, exploiting the energy from ubiquinone reduction by NADH to drive protons across the energy-transducing inner membrane. Recent cryo-EM analyses of mammalian and yeast complex I have revolutionized structural and mechanistic knowledge and defined structures in different functional states. Here, we describe a 2.7-Å-resolution structure of the 42-subunit complex I from the yeast Yarrowia lipolytica containing 275 structured water molecules. We identify a proton-relay pathway for ubiquinone reduction and water molecules that connect mechanistically crucial elements and constitute proton-translocation pathways through the membrane. By comparison with known structures, we deconvolute structural changes governing the mammalian 'deactive transition' (relevant to ischemia-reperfusion injury) and their effects on the ubiquinone-binding site and a connected cavity in ND1. Our structure thus provides important insights into catalysis by this enigmatic respiratory machine.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Binding Sites
  • Catalysis
  • Crystallography, X-Ray
  • Electron Transport Complex I / chemistry*
  • Electron Transport Complex I / metabolism*
  • Models, Molecular
  • Protein Conformation
  • Protein Domains
  • Protein Subunits
  • Protons
  • Ubiquinone / analogs & derivatives
  • Ubiquinone / chemistry
  • Ubiquinone / metabolism
  • Water / metabolism
  • Yarrowia / chemistry*


  • Protein Subunits
  • Protons
  • Water
  • Ubiquinone
  • Electron Transport Complex I
  • coenzyme Q10