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Cryo-EM structures define ubiquinone-10 binding to mitochondrial complex I and conformational transitions accompanying Q-site occupancy

Author

Listed:
  • Injae Chung

    (MRC Mitochondrial Biology Unit, University of Cambridge, The Keith Peters Building, Cambridge Biomedical Campus, Hills Road)

  • John J. Wright

    (MRC Mitochondrial Biology Unit, University of Cambridge, The Keith Peters Building, Cambridge Biomedical Campus, Hills Road)

  • Hannah R. Bridges

    (MRC Mitochondrial Biology Unit, University of Cambridge, The Keith Peters Building, Cambridge Biomedical Campus, Hills Road)

  • Bozhidar S. Ivanov

    (MRC Mitochondrial Biology Unit, University of Cambridge, The Keith Peters Building, Cambridge Biomedical Campus, Hills Road)

  • Olivier Biner

    (MRC Mitochondrial Biology Unit, University of Cambridge, The Keith Peters Building, Cambridge Biomedical Campus, Hills Road
    Institute of Plant and Microbial Biology, University of Zurich)

  • Caroline S. Pereira

    (Instituto de Química, Universidade de São Paulo)

  • Guilherme M. Arantes

    (Instituto de Química, Universidade de São Paulo)

  • Judy Hirst

    (MRC Mitochondrial Biology Unit, University of Cambridge, The Keith Peters Building, Cambridge Biomedical Campus, Hills Road)

Abstract

Mitochondrial complex I is a central metabolic enzyme that uses the reducing potential of NADH to reduce ubiquinone-10 (Q10) and drive four protons across the inner mitochondrial membrane, powering oxidative phosphorylation. Although many complex I structures are now available, the mechanisms of Q10 reduction and energy transduction remain controversial. Here, we reconstitute mammalian complex I into phospholipid nanodiscs with exogenous Q10. Using cryo-EM, we reveal a Q10 molecule occupying the full length of the Q-binding site in the ‘active’ (ready-to-go) resting state together with a matching substrate-free structure, and apply molecular dynamics simulations to propose how the charge states of key residues influence the Q10 binding pose. By comparing ligand-bound and ligand-free forms of the ‘deactive’ resting state (that require reactivating to catalyse), we begin to define how substrate binding restructures the deactive Q-binding site, providing insights into its physiological and mechanistic relevance.

Suggested Citation

  • Injae Chung & John J. Wright & Hannah R. Bridges & Bozhidar S. Ivanov & Olivier Biner & Caroline S. Pereira & Guilherme M. Arantes & Judy Hirst, 2022. "Cryo-EM structures define ubiquinone-10 binding to mitochondrial complex I and conformational transitions accompanying Q-site occupancy," Nature Communications, Nature, vol. 13(1), pages 1-13, December.
  • Handle: RePEc:nat:natcom:v:13:y:2022:i:1:d:10.1038_s41467-022-30506-1
    DOI: 10.1038/s41467-022-30506-1
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    References listed on IDEAS

    as
    1. Jiapeng Zhu & Kutti R. Vinothkumar & Judy Hirst, 2016. "Structure of mammalian respiratory complex I," Nature, Nature, vol. 536(7616), pages 354-358, August.
    2. Tsang, Eric W. K., 2014. "Old and New," Management and Organization Review, Cambridge University Press, vol. 10(03), pages 390-390, November.
    3. Etienne Galemou Yoga & Kristian Parey & Amina Djurabekova & Outi Haapanen & Karin Siegmund & Klaus Zwicker & Vivek Sharma & Volker Zickermann & Heike Angerer, 2020. "Essential role of accessory subunit LYRM6 in the mechanism of mitochondrial complex I," Nature Communications, Nature, vol. 11(1), pages 1-8, December.
    4. Zhan Yin & Nils Burger & Duvaraka Kula-Alwar & Dunja Aksentijević & Hannah R. Bridges & Hiran A. Prag & Daniel N. Grba & Carlo Viscomi & Andrew M. James & Amin Mottahedin & Thomas Krieg & Michael P. M, 2021. "Structural basis for a complex I mutation that blocks pathological ROS production," Nature Communications, Nature, vol. 12(1), pages 1-12, December.
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