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A giant molecular proton pump: structure and mechanism of respiratory complex I

Nature Reviews Molecular Cell Biology volume 16, pages 375–388 (2015)Cite this article

Subjects

Key Points

  • The electron transport chain (ETC) is crucial for life, as it is essential for cellular ATP production.

  • Most ETC enzymes are large multi-subunit protein assemblies. Of these, complex I is the largest and most elaborate, and such complexity has made it difficult to elucidate the details of its function.

  • The bacterial complex I represents the minimal version of the enzyme and has 14 conserved subunits that are necessary and essential for function. The subunits are shared between the peripheral arm (where electron transfer takes place) and the membrane arm (which carries out proton translocation).

  • The mitochondrial enzyme shares this structure and has acquired supernumerary subunits.

  • Novel insights have recently been obtained on the evolution of antiporter-like subunits of complex I, which are part of the membrane arm, from the Mrp family of antiporters.

  • The mechanism of complex I is unique in that it must couple the spatially separated electron transfer and proton translocation pathways.

  • The mechanism of coupling between electron transfer and proton translocation probably involves long-range conformational changes driven mainly by quinone redox reactions.

Abstract

The mitochondrial respiratory chain, also known as the electron transport chain (ETC), is crucial to life, and energy production in the form of ATP is the main mitochondrial function. Three proton-translocating enzymes of the ETC, namely complexes I, III and IV, generate proton motive force, which in turn drives ATP synthase (complex V). The atomic structures and basic mechanisms of most respiratory complexes have previously been established, with the exception of complex I, the largest complex in the ETC. Recently, the crystal structure of the entire complex I was solved using a bacterial enzyme. The structure provided novel insights into the core architecture of the complex, the electron transfer and proton translocation pathways, as well as the mechanism that couples these two processes.

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Figure 1: The electron transport chain.
Figure 2: Structure of Thermus thermophilus complex I.
Figure 3: Proton translocation channels.
Figure 4: Proposed coupling mechanism of complex I.

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Acknowledgements

The work in the author's laboratory in the Medical Research Council Mitochondrial Biology Unit (Cambridge, UK) was funded by the UK Medical Research Council. Additional funding was provided by the Royal Society and the European Molecular Biology Organization (EMBO).

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  1. Institute of Science and Technology Austria, Klosterneuburg, 3400, Austria

    Leonid A. Sazanov

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Supplementary information

Supplementary information S1 (figure)

Central hydrophilic axis. (PDF 3048 kb)

Supplementary information S2 (figure)

Detailed analysis of possible pathways for proton translocation. (PDF 3329 kb)

Supplementary information S3 (figure)

Conservation of surface-exposed residues in the membrane domain of complex I. (PDF 5142 kb)

Supplementary information S4 (figure)

The most common primary human LHON mutations, mapped onto bacterial complex I structures. (PDF 2704 kb)

PowerPoint slides

Glossary

Chemiosmotic coupling

A process that links the electron transport chain to ATP synthesis.

Midpoint redox potential

(Em). A measure of the tendency of a chemical species to acquire electrons and thereby be reduced. The species with large positive potential have high affinity for electrons and vice versa. Em denotes the potential at which the compound is half oxidized and half reduced.

Molybdopterin

A class of redox cofactors found in molybdenum- and tungsten-containing enzymes, such as nitrate reductase.

[NiFe] hydrogenases

The class of hydrogenases with the most members. [NiFe] hydrogenases catalyse the reversible 2H+ + 2e− ↔ H2 reaction; their core comprises the large subunit hosting the Ni–Fe active site and the small subunit hosting the Fe–S clusters.

π-bulge

(Also known as π–helix). A protein feature created by the insertion of a single additional amino acid into a pre-existing α-helix, destabilizing secondary structure in potential functional sites.

Grotthuss-type mechanism

A proton-hopping mechanism, whereby protons travel through networks of water molecules and protonatable side chains via the formation and cleavage of hydrogen bonds.

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Sazanov, L. A giant molecular proton pump: structure and mechanism of respiratory complex I. Nat Rev Mol Cell Biol 16, 375–388 (2015). https://doi.org/10.1038/nrm3997

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