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

Accepted version
Peer-reviewed

Type

Article

Change log

Authors

Agip, Ahmed-Noor A 
Bridges, Hannah R 
Viscomi, Carlo 
Rawson, Shaun 

Abstract

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.

Description

Keywords

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

Journal Title

Nat Struct Mol Biol

Conference Name

Journal ISSN

1545-9993
1545-9985

Volume Title

25

Publisher

Springer Science and Business Media LLC
Sponsorship
Medical Research Council (MC_U105663141)
MRC (MC_UP_1002/1)
Medical Research Council (MC_UP_1002/1)
MRC (MC_UP_1002/1)
Medical Research Council (MC_UU_00015/8)
MRC (MC_UU_00015/2)
MRC (MC_UU_00015/8)
Medical Research Council (MC_UU_00015/7)