Na+ controls hypoxic signalling by the mitochondrial respiratory chain

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 Cortés, Ana Victoria Lechuga-Vieco, Pooja Jadiya, Elisa Navarro, Esther Parada, Alejandra Palomino-Antolín, Daniel Tello, Rebeca Acín-Pérez, Juan Carlos Rodríguez-Aguilera, Plácido Navas, Ángel Cogolludo, Iván López-Montero, Álvaro Martínez-del-Pozo, Javier Egea, Manuela G. López, John W. Elrod, Jesús Ruíz-Cabello, Anna Bogdanova, José Antonio Enríquez () and Antonio Martínez-Ruiz ()
Additional contact information
Pablo Hernansanz-Agustín: Unidad de Investigación, Hospital Universitario Santa Cristina, Instituto de Investigación Sanitaria Princesa (IIS-IP)
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)
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)
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
Ana Victoria Lechuga-Vieco: Centro Nacional de Investigaciones Cardiovasculares Carlos III (CNIC)
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)
Alejandra Palomino-Antolín: Unidad de Investigación, Hospital Universitario Santa Cristina, 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)
Juan Carlos Rodríguez-Aguilera: Universidad Pablo de Olavide-CSIC
Plácido Navas: Universidad Pablo de Olavide-CSIC
Ángel Cogolludo: Centro de Investigación Biomédica en Red de Enfermedades Respiratorias (CIBERES)
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)
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)
Anna Bogdanova: University of Zurich
José Antonio Enríquez: Centro Nacional de Investigaciones Cardiovasculares Carlos III (CNIC)
Antonio Martínez-Ruiz: Unidad de Investigación, Hospital Universitario Santa Cristina, Instituto de Investigación Sanitaria Princesa (IIS-IP)

Nature, 2020, vol. 586, issue 7828, 287-291

Abstract: 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.

Date: 2020
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DOI: 10.1038/s41586-020-2551-y

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