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Transgenic NADH dehydrogenase restores oxygen regulation of breathing in mitochondrial complex I-deficient mice

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  • Blanca Jiménez-Gómez

    (Hospital Universitario Virgen del Rocío/CSIC/Universidad de Sevilla
    Universidad de Sevilla
    Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED))

  • Patricia Ortega-Sáenz

    (Hospital Universitario Virgen del Rocío/CSIC/Universidad de Sevilla
    Universidad de Sevilla
    Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED))

  • Lin Gao

    (Hospital Universitario Virgen del Rocío/CSIC/Universidad de Sevilla
    Universidad de Sevilla
    Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED))

  • Patricia González-Rodríguez

    (Hospital Universitario Virgen del Rocío/CSIC/Universidad de Sevilla
    Universidad de Sevilla
    Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED))

  • Paula García-Flores

    (Hospital Universitario Virgen del Rocío/CSIC/Universidad de Sevilla
    Universidad de Sevilla
    Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED))

  • Navdeep Chandel

    (Northwestern University)

  • José López-Barneo

    (Hospital Universitario Virgen del Rocío/CSIC/Universidad de Sevilla
    Universidad de Sevilla
    Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED))

Abstract

The hypoxic ventilatory response (HVR) is a life-saving reflex, triggered by the activation of chemoreceptor glomus cells in the carotid body (CB) connected with the brainstem respiratory center. The molecular mechanisms underlying glomus cell acute oxygen (O2) sensing are unclear. Genetic disruption of mitochondrial complex I (MCI) selectively abolishes the HVR and glomus cell responsiveness to hypoxia. However, it is unknown what functions of MCI (metabolic, proton transport, or signaling) are essential for O2 sensing. Here we show that transgenic mitochondrial expression of NDI1, a single-molecule yeast NADH/quinone oxidoreductase that does not directly contribute to proton pumping, fully recovers the HVR and glomus cell sensitivity to hypoxia in MCI-deficient mice. Therefore, maintenance of mitochondrial NADH dehydrogenase activity and the electron transport chain are absolutely necessary for O2-dependent regulation of breathing. NDI1 expression also rescues other systemic defects caused by MCI deficiency. These data explain the role of MCI in acute O2 sensing by arterial chemoreceptors and demonstrate the optimal recovery of complex organismal functions by gene therapy.

Suggested Citation

  • 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.
  • Handle: RePEc:nat:natcom:v:14:y:2023:i:1:d:10.1038_s41467-023-36894-2
    DOI: 10.1038/s41467-023-36894-2
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    as
    1. David A. Stroud & Elliot E. Surgenor & Luke E. Formosa & Boris Reljic & Ann E. Frazier & Marris G. Dibley & Laura D. Osellame & Tegan Stait & Traude H. Beilharz & David R. Thorburn & Agus Salim & Mich, 2016. "Accessory subunits are integral for assembly and function of human mitochondrial complex I," Nature, Nature, vol. 538(7623), pages 123-126, October.
    2. Patricia González-Rodríguez & Enrico Zampese & Kristen A. Stout & Jaime N. Guzman & Ema Ilijic & Ben Yang & Tatiana Tkatch & Mihaela A. Stavarache & David L. Wokosin & Lin Gao & Michael G. Kaplitt & J, 2021. "Disruption of mitochondrial complex I induces progressive parkinsonism," Nature, Nature, vol. 599(7886), pages 650-656, November.
    3. Pablo Hernansanz-Agustín & Carmen Choya-Foces & Susana Carregal-Romero & Elena Ramos & Tamara Oliva & Tamara Villa-Piña & Laura Moreno & Alicia Izquierdo-Álvarez & J. Daniel Cabrera-García & Ana Corté, 2020. "Na+ controls hypoxic signalling by the mitochondrial respiratory chain," Nature, Nature, vol. 586(7828), pages 287-291, October.
    4. Jiapeng Zhu & Kutti R. Vinothkumar & Judy Hirst, 2016. "Structure of mammalian respiratory complex I," Nature, Nature, vol. 536(7616), pages 354-358, August.
    5. Hortensia Torres-Torrelo & Patricia Ortega-Sáenz & Lin Gao & José López-Barneo, 2021. "Lactate sensing mechanisms in arterial chemoreceptor cells," Nature Communications, Nature, vol. 12(1), pages 1-13, December.
    6. Eugenio F. Fornasiero & Sunit Mandad & Hanna Wildhagen & Mihai Alevra & Burkhard Rammner & Sarva Keihani & Felipe Opazo & Inga Urban & Till Ischebeck & M. Sadman Sakib & Maryam K. Fard & Koray Kirli &, 2018. "Precisely measured protein lifetimes in the mouse brain reveal differences across tissues and subcellular fractions," Nature Communications, Nature, vol. 9(1), pages 1-17, December.
    7. Mathew Tantama & Juan Ramón Martínez-François & Rebecca Mongeon & Gary Yellen, 2013. "Imaging energy status in live cells with a fluorescent biosensor of the intracellular ATP-to-ADP ratio," Nature Communications, Nature, vol. 4(1), pages 1-11, December.
    8. Yue Feng & Wenfei Li & Jian Li & Jiawei Wang & Jingpeng Ge & Duo Xu & Yanjing Liu & Kaiqi Wu & Qingyin Zeng & Jia-Wei Wu & Changlin Tian & Bing Zhou & Maojun Yang, 2012. "Structural insight into the type-II mitochondrial NADH dehydrogenases," Nature, Nature, vol. 491(7424), pages 478-482, November.
    9. 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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