Towards a mechanistic model for redox-driven proton pumping in respiratory complex I

Single-particle electron cryomicroscopy (cryo-EM) has led to a revolution in structural work on mammalian respiratory complex I. Complex I (mitochondrial NADH:ubiquinone oxidoreductase), a membrane-bound redox-driven proton pump, is one of the largest and most complicated enzymes in the mammalian cell. Rapid progress, following the first 5-Å resolution data on bovine complex I in 2014, has led to a model for mouse complex I at 3.3-Å resolution that contains 96% of the 8,518 residues and to the identification of different particle classes, some of which are assigned to biochemically defined states. Factors that helped improve resolution, including improvements to biochemistry, cryo-EM grid preparation, data collection strategy, and image processing, are discussed. Together with recent structural data from an ancient relative, membrane-bound hydrogenase, cryo-EM on mammalian complex I has provided new insights into the proton-pumping machinery and a foundation for understanding the enzyme's catalytic mechanism.

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The proton-pumping respiratory complex I of bacteria and mitochondria and its homologue in chloroplasts

FEBS Letters ◽

10.1016/0014-5793(95)00548-n ◽

1995 ◽

Vol 367 (2) ◽

pp. 107-111 ◽

Cited By ~ 188

Author(s):

Thorsten Friedrich ◽

Klaus Steinmüller ◽

Hanns Weiss

Keyword(s):

Complex I ◽

Proton Pumping ◽

Respiratory Complex ◽

Respiratory Complex I

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How cardiolipin modulates the dynamics of respiratory complex I

Science Advances ◽

10.1126/sciadv.aav1850 ◽

2019 ◽

Vol 5 (3) ◽

pp. eaav1850 ◽

Cited By ~ 20

Author(s):

Alexander Jussupow ◽

Andrea Di Luca ◽

Ville R. I. Kaila

Keyword(s):

Conformational Changes ◽

Complex I ◽

Specific Interaction ◽

Proton Pumping ◽

Respiratory Enzymes ◽

Respiratory Complex ◽

Respiratory Chains ◽

Membrane Bound ◽

Respiratory Complex I ◽

Structure And Activity

Cardiolipin modulates the activity of membrane-bound respiratory enzymes that catalyze biological energy transduction. The respiratory complex I functions as the primary redox-driven proton pump in mitochondrial and bacterial respiratory chains, and its activity is strongly enhanced by cardiolipin. However, despite recent advances in the structural biology of complex I, cardiolipin-specific interaction mechanisms currently remain unknown. On the basis of millisecond molecular simulations, we suggest that cardiolipin binds to proton-pumping subunits of complex I and induces global conformational changes that modulate the accessibility of the quinone substrate to the enzyme. Our findings provide key information on the coupling between complex I dynamics and activity and suggest how biological membranes modulate the structure and activity of proteins.

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Long-range proton-coupled electron transfer in biological energy conversion: towards mechanistic understanding of respiratory complex I

Journal of The Royal Society Interface ◽

10.1098/rsif.2017.0916 ◽

2018 ◽

Vol 15 (141) ◽

pp. 20170916 ◽

Cited By ~ 46

Author(s):

Ville R. I. Kaila

Keyword(s):

Energy Conversion ◽

Complex I ◽

Mechanistic Model ◽

Atomic Scale ◽

Respiratory Complex ◽

Proton Coupled Electron Transfer ◽

Transduction Mechanisms ◽

Molecular Machinery ◽

Respiratory Complex I ◽

Action At A Distance

Biological energy conversion is driven by efficient enzymes that capture, store and transfer protons and electrons across large distances. Recent advances in structural biology have provided atomic-scale blueprints of these types of remarkable molecular machinery, which together with biochemical, biophysical and computational experiments allow us to derive detailed energy transduction mechanisms for the first time. Here, I present one of the most intricate and least understood types of biological energy conversion machinery, the respiratory complex I, and how its redox-driven proton-pump catalyses charge transfer across approximately 300 Å distances. After discussing the functional elements of complex I, a putative mechanistic model for its action-at-a-distance effect is presented, and functional parallels are drawn to other redox- and light-driven ion pumps.

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