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Na+ controls hypoxic signalling by the mitochondrial respiratory chain

Author

Listed:
  • Pablo Hernansanz-Agustín

    (Unidad de Investigación, Hospital Universitario Santa Cristina, Instituto de Investigación Sanitaria Princesa (IIS-IP)
    Centro Nacional de Investigaciones Cardiovasculares Carlos III (CNIC))

  • Carmen Choya-Foces

    (Unidad de Investigación, Hospital Universitario Santa Cristina, Instituto de Investigación Sanitaria Princesa (IIS-IP))

  • Susana Carregal-Romero

    (Center for Cooperative Research in Biomaterials (CIC biomaGUNE), Basque Research and Technology Alliance (BRTA)
    Centro de Investigación Biomédica en Red de Enfermedades Respiratorias (CIBERES))

  • Elena Ramos

    (Servicio de Inmunología, Hospital Universitario de La Princesa, Instituto de Investigación Sanitaria Princesa (IIS-IP))

  • Tamara Oliva

    (Unidad de Investigación, Hospital Universitario Santa Cristina, Instituto de Investigación Sanitaria Princesa (IIS-IP))

  • Tamara Villa-Piña

    (Servicio de Inmunología, Hospital Universitario de La Princesa, Instituto de Investigación Sanitaria Princesa (IIS-IP))

  • Laura Moreno

    (Centro de Investigación Biomédica en Red de Enfermedades Respiratorias (CIBERES)
    Departamento de Farmacología y Toxicología, Facultad de Medicina, Universidad Complutense de Madrid (UCM), Instituto de Investigación Sanitaria Gregorio Marañón (IISGM))

  • Alicia Izquierdo-Álvarez

    (Servicio de Inmunología, Hospital Universitario de La Princesa, Instituto de Investigación Sanitaria Princesa (IIS-IP))

  • J. Daniel Cabrera-García

    (Unidad de Investigación, Hospital Universitario Santa Cristina, Instituto de Investigación Sanitaria Princesa (IIS-IP))

  • Ana Cortés

    (Universidad Pablo de Olavide-CSIC
    Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER))

  • Ana Victoria Lechuga-Vieco

    (Centro Nacional de Investigaciones Cardiovasculares Carlos III (CNIC)
    Centro de Investigación Biomédica en Red de Enfermedades Respiratorias (CIBERES))

  • Pooja Jadiya

    (Temple University)

  • Elisa Navarro

    (Instituto Teófilo Hernando, Departamento de Farmacología y Terapéutica, Facultad de Medicina, Universidad Autónoma de Madrid (UAM), Instituto de Investigación Sanitaria Princesa (IIS-IP))

  • Esther Parada

    (Unidad de Investigación, Hospital Universitario Santa Cristina, Instituto de Investigación Sanitaria Princesa (IIS-IP)
    Instituto Teófilo Hernando, Departamento de Farmacología y Terapéutica, Facultad de Medicina, Universidad Autónoma de Madrid (UAM), Instituto de Investigación Sanitaria Princesa (IIS-IP))

  • Alejandra Palomino-Antolín

    (Unidad de Investigación, Hospital Universitario Santa Cristina, Instituto de Investigación Sanitaria Princesa (IIS-IP)
    Instituto Teófilo Hernando, Departamento de Farmacología y Terapéutica, Facultad de Medicina, Universidad Autónoma de Madrid (UAM), Instituto de Investigación Sanitaria Princesa (IIS-IP))

  • Daniel Tello

    (Unidad de Investigación, Hospital Universitario Santa Cristina, Instituto de Investigación Sanitaria Princesa (IIS-IP))

  • Rebeca Acín-Pérez

    (Centro Nacional de Investigaciones Cardiovasculares Carlos III (CNIC)
    David Geffen School of Medicine at University of California Los Angeles (UCLA)
    David Geffen School of Medicine at University of California Los Angeles (UCLA))

  • Juan Carlos Rodríguez-Aguilera

    (Universidad Pablo de Olavide-CSIC
    Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER))

  • Plácido Navas

    (Universidad Pablo de Olavide-CSIC
    Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER))

  • Ángel Cogolludo

    (Centro de Investigación Biomédica en Red de Enfermedades Respiratorias (CIBERES)
    Departamento de Farmacología y Toxicología, Facultad de Medicina, Universidad Complutense de Madrid (UCM), Instituto de Investigación Sanitaria Gregorio Marañón (IISGM))

  • Iván López-Montero

    (Universidad Complutense de Madrid (UCM), Instituto de Investigación Sanitaria Hospital “12 de Octubre” (imas12))

  • Álvaro Martínez-del-Pozo

    (Universidad Complutense de Madrid (UCM))

  • Javier Egea

    (Unidad de Investigación, Hospital Universitario Santa Cristina, Instituto de Investigación Sanitaria Princesa (IIS-IP)
    Instituto Teófilo Hernando, Departamento de Farmacología y Terapéutica, Facultad de Medicina, Universidad Autónoma de Madrid (UAM), Instituto de Investigación Sanitaria Princesa (IIS-IP))

  • Manuela G. López

    (Instituto Teófilo Hernando, Departamento de Farmacología y Terapéutica, Facultad de Medicina, Universidad Autónoma de Madrid (UAM), Instituto de Investigación Sanitaria Princesa (IIS-IP))

  • John W. Elrod

    (Temple University)

  • Jesús Ruíz-Cabello

    (Center for Cooperative Research in Biomaterials (CIC biomaGUNE), Basque Research and Technology Alliance (BRTA)
    Centro de Investigación Biomédica en Red de Enfermedades Respiratorias (CIBERES)
    Ikerbasque, Basque Foundation for Science
    Universidad Complutense de Madrid (UCM))

  • Anna Bogdanova

    (University of Zurich)

  • José Antonio Enríquez

    (Centro Nacional de Investigaciones Cardiovasculares Carlos III (CNIC)
    Centro de Investigación Biomédica en Red de Fragilidad y Envejecimiento Saludable (CIBERFES))

  • Antonio Martínez-Ruiz

    (Unidad de Investigación, Hospital Universitario Santa Cristina, Instituto de Investigación Sanitaria Princesa (IIS-IP)
    Universidad Complutense de Madrid (UCM)
    Centro de Investigación Biomédica en Red de Enfermedades Cardiovasculares (CIBERCV))

Abstract

All metazoans depend on the consumption of O2 by the mitochondrial oxidative phosphorylation system (OXPHOS) to produce energy. In addition, the OXPHOS uses O2 to produce reactive oxygen species that can drive cell adaptations1–4, a phenomenon that occurs in hypoxia4–8 and whose precise mechanism remains unknown. Ca2+ is the best known ion that acts as a second messenger9, yet the role ascribed to Na+ is to serve as a mere mediator of membrane potential10. Here we show that Na+ acts as a second messenger that regulates OXPHOS function and the production of reactive oxygen species by modulating the fluidity of the inner mitochondrial membrane. A conformational shift in mitochondrial complex I during acute hypoxia11 drives acidification of the matrix and the release of free Ca2+ from calcium phosphate (CaP) precipitates. The concomitant activation of the mitochondrial Na+/Ca2+ exchanger promotes the import of Na+ into the matrix. Na+ interacts with phospholipids, reducing inner mitochondrial membrane fluidity and the mobility of free ubiquinone between complex II and complex III, but not inside supercomplexes. As a consequence, superoxide is produced at complex III. The inhibition of Na+ import through the Na+/Ca2+ exchanger is sufficient to block this pathway, preventing adaptation to hypoxia. These results reveal that Na+ controls OXPHOS function and redox signalling through an unexpected interaction with phospholipids, with profound consequences for cellular metabolism.

Suggested Citation

  • 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.
  • Handle: RePEc:nat:nature:v:586:y:2020:i:7828:d:10.1038_s41586-020-2551-y
    DOI: 10.1038/s41586-020-2551-y
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    Cited by:

    1. 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.

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