Cryo-EM structures of complex I from mouse heart mitochondria in two biochemically defined states

Nat Struct Mol Biol. 2018 Jul;25(7):548-556. doi: 10.1038/s41594-018-0073-1. Epub 2018 Jun 18.


Complex I (NADH:ubiquinone oxidoreductase) uses the reducing potential of NADH to drive protons across the energy-transducing inner membrane and power oxidative phosphorylation in mammalian mitochondria. Recent cryo-EM analyses have produced near-complete models of all 45 subunits in the bovine, ovine and porcine complexes and have identified two states relevant to complex I in ischemia-reperfusion injury. Here, we describe the 3.3-Å structure of complex I from mouse heart mitochondria, a biomedically relevant model system, in the 'active' state. We reveal a nucleotide bound in subunit NDUFA10, a nucleoside kinase homolog, and define mechanistically critical elements in the mammalian enzyme. By comparisons with a 3.9-Å structure of the 'deactive' state and with known bacterial structures, we identify differences in helical geometry in the membrane domain that occur upon activation or that alter the positions of catalytically important charged residues. Our results demonstrate the capability of cryo-EM analyses to challenge and develop mechanistic models for mammalian complex I.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Binding Sites
  • Cryoelectron Microscopy
  • Electron Transport Complex I / chemistry*
  • Electron Transport Complex I / metabolism
  • Electron Transport Complex I / ultrastructure
  • Enzyme Activation
  • Mice
  • Mitochondria, Heart / enzymology*
  • Models, Molecular
  • NADH Dehydrogenase / chemistry
  • NADH Dehydrogenase / metabolism
  • NADH Dehydrogenase / ultrastructure
  • Nucleotides / chemistry
  • Nucleotides / metabolism
  • Phospholipids / chemistry
  • Phospholipids / metabolism
  • Protein Structural Elements
  • Protein Structure, Quaternary
  • Protein Subunits
  • Ubiquinone / chemistry
  • Ubiquinone / metabolism


  • Nucleotides
  • Phospholipids
  • Protein Subunits
  • Ubiquinone
  • NADH Dehydrogenase
  • NdufA10 protein, mouse
  • Electron Transport Complex I