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Structural basis for a complex I mutation that blocks pathological ROS production

Author

Listed:
  • Zhan Yin

    (University of Cambridge)

  • Nils Burger

    (University of Cambridge)

  • Duvaraka Kula-Alwar

    (University of Cambridge)

  • Dunja Aksentijević

    (Queen Mary University of London
    Queen Mary University of London)

  • Hannah R. Bridges

    (University of Cambridge)

  • Hiran A. Prag

    (University of Cambridge)

  • Daniel N. Grba

    (University of Cambridge)

  • Carlo Viscomi

    (University of Cambridge
    University of Padova via Ugo Bassi 58/B)

  • Andrew M. James

    (University of Cambridge)

  • Amin Mottahedin

    (University of Cambridge
    University of Cambridge
    Institute of Neuroscience and Physiology, Sahlgrenska Academy, University of Gothenburg)

  • Thomas Krieg

    (University of Cambridge)

  • Michael P. Murphy

    (University of Cambridge
    University of Cambridge)

  • Judy Hirst

    (University of Cambridge)

Abstract

Mitochondrial complex I is central to the pathological reactive oxygen species (ROS) production that underlies cardiac ischemia–reperfusion (IR) injury. ND6-P25L mice are homoplasmic for a disease-causing mtDNA point mutation encoding the P25L substitution in the ND6 subunit of complex I. The cryo-EM structure of ND6-P25L complex I revealed subtle structural changes that facilitate rapid conversion to the “deactive” state, usually formed only after prolonged inactivity. Despite its tendency to adopt the “deactive” state, the mutant complex is fully active for NADH oxidation, but cannot generate ROS by reverse electron transfer (RET). ND6-P25L mitochondria function normally, except for their lack of RET ROS production, and ND6-P25L mice are protected against cardiac IR injury in vivo. Thus, this single point mutation in complex I, which does not affect oxidative phosphorylation but renders the complex unable to catalyse RET, demonstrates the pathological role of ROS production by RET during IR injury.

Suggested Citation

  • 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.
    • Handle: RePEc:nat:natcom:v:12:y:2021:i:1:d:10.1038_s41467-021-20942-w
    DOI: 10.1038/s41467-021-20942-w
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    Cited by:

    1. 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.
    2. Blanca Jiménez-Gómez & Patricia Ortega-Sáenz & Lin Gao & Patricia González-Rodríguez & Paula García-Flores & Navdeep Chandel & José López-Barneo, 2023. "Transgenic NADH dehydrogenase restores oxygen regulation of breathing in mitochondrial complex I-deficient mice," Nature Communications, Nature, vol. 14(1), pages 1-14, December.
    3. John O. Onukwufor & M. Arsalan Farooqi & Anežka Vodičková & Shon A. Koren & Aksana Baldzizhar & Brandon J. Berry & Gisela Beutner & George A. Porter & Vsevolod Belousov & Alan Grossfield & Andrew P. W, 2022. "A reversible mitochondrial complex I thiol switch mediates hypoxic avoidance behavior in C. elegans," Nature Communications, Nature, vol. 13(1), pages 1-14, December.

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