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A reversible mitochondrial complex I thiol switch mediates hypoxic avoidance behavior in C. elegans

Author

Listed:
  • John O. Onukwufor

    (University of Rochester Medical Center
    University of Rochester Medical Center)

  • M. Arsalan Farooqi

    (University of Rochester Medical Center)

  • Anežka Vodičková

    (University of Rochester Medical Center)

  • Shon A. Koren

    (University of Rochester Medical Center)

  • Aksana Baldzizhar

    (University of Rochester Medical Center)

  • Brandon J. Berry

    (University of Rochester Medical Center)

  • Gisela Beutner

    (University of Rochester Medical Center)

  • George A. Porter

    (University of Rochester Medical Center
    University of Rochester Medical Center)

  • Vsevolod Belousov

    (Pirogov Russian National Research Medical University
    Federal Center of Brain Research and Neurotechnologies, FMBA)

  • Alan Grossfield

    (University of Rochester Medical Center)

  • Andrew P. Wojtovich

    (University of Rochester Medical Center
    University of Rochester Medical Center)

Abstract

C. elegans react to metabolic distress caused by mismatches in oxygen and energy status via distinct behavioral responses. At the molecular level, these responses are coordinated by under-characterized, redox-sensitive processes, thought to initiate in mitochondria. Complex I of the electron transport chain is a major site of reactive oxygen species (ROS) production and is canonically associated with oxidative damage following hypoxic exposure. Here, we use a combination of optogenetics and CRISPR/Cas9-mediated genome editing to exert spatiotemporal control over ROS production. We demonstrate a photo-locomotory remodeling of avoidance behavior by local ROS production due to the reversible oxidation of a single thiol on the complex I subunit NDUF-2.1. Reversible thiol oxidation at this site is necessary and sufficient for the behavioral response to hypoxia, does not respond to ROS produced at more distal sites, and protects against lethal hypoxic exposure. Molecular modeling suggests that oxidation at this thiol residue alters the ability for NDUF-2.1 to coordinate electron transfer to coenzyme Q by destabilizing the Q-binding pocket, causing decreased complex I activity. Overall, site-specific ROS production regulates behavioral responses and these findings provide a mechanistic target to suppress the detrimental effects of hypoxia.

Suggested Citation

  • 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.
    • Handle: RePEc:nat:natcom:v:13:y:2022:i:1:d:10.1038_s41467-022-30169-y
    DOI: 10.1038/s41467-022-30169-y
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    References listed on IDEAS

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    1. Guang Li & Jianke Gong & Haoyun Lei & Jianfeng Liu & X. Z. Shawn Xu, 2016. "Promotion of behavior and neuronal function by reactive oxygen species in C. elegans," Nature Communications, Nature, vol. 7(1), pages 1-12, December.
    2. Edward T. Chouchani & Victoria R. Pell & Edoardo Gaude & Dunja Aksentijević & Stephanie Y. Sundier & Ellen L. Robb & Angela Logan & Sergiy M. Nadtochiy & Emily N. J. Ord & Anthony C. Smith & Filmon Ey, 2014. "Ischaemic accumulation of succinate controls reperfusion injury through mitochondrial ROS," Nature, Nature, vol. 515(7527), pages 431-435, November.
    3. 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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    Cited by:

    1. Shon A. Koren & Nada Ahmed Selim & Lizbeth Rosa & Jacob Horn & M. Arsalan Farooqi & Alicia Y. Wei & Annika Müller-Eigner & Jacen Emerson & Gail V. W. Johnson & Andrew P. Wojtovich, 2023. "All-optical spatiotemporal mapping of ROS dynamics across mitochondrial microdomains in situ," Nature Communications, Nature, vol. 14(1), pages 1-16, December.

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