by Hernansanz-Agustín, Pablo, Choya-Foces, Carmen, Carregal-Romero, Susana, Ramos, Elena, Oliva, Tamara, Villa-Piña, Tamara, Moreno, Laura, Izquierdo-Álvarez, Alicia, Cabrera-García, J Daniel, Cortés, Ana, Lechuga-Vieco, Ana Victoria, Jadiya, Pooja, Navarro, Elisa, Parada, Esther, Palomino-Antolín, Alejandra, Tello, Daniel, Acín-Pérez, Rebeca, Rodríguez-Aguilera, Juan Carlos, Navas, Plácido, Cogolludo, Angel, López-Montero, Iván, Martínez-Del-Pozo, Álvaro, Egea, Javier, López, Manuela G, Elrod, John W, Ruiz-Cabello, Jesus, Bogdanova, Anna, Enríquez, José Antonio and Martínez-Ruiz, Antonio
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.
Reference:
Na+ controls hypoxic signalling by the mitochondrial respiratory chain. (Hernansanz-Agustín, Pablo, Choya-Foces, Carmen, Carregal-Romero, Susana, Ramos, Elena, Oliva, Tamara, Villa-Piña, Tamara, Moreno, Laura, Izquierdo-Álvarez, Alicia, Cabrera-García, J Daniel, Cortés, Ana, Lechuga-Vieco, Ana Victoria, Jadiya, Pooja, Navarro, Elisa, Parada, Esther, Palomino-Antolín, Alejandra, Tello, Daniel, Acín-Pérez, Rebeca, Rodríguez-Aguilera, Juan Carlos, Navas, Plácido, Cogolludo, Angel, López-Montero, Iván, Martínez-Del-Pozo, Álvaro, Egea, Javier, López, Manuela G, Elrod, John W, Ruiz-Cabello, Jesus, Bogdanova, Anna, Enríquez, José Antonio and Martínez-Ruiz, Antonio), In Nature, Nature Publishing Group, volume 48, 2020.
Bibtex Entry:
@article{HernansanzAgustin:2020bw,
author = {Hernansanz-Agust{'i}n, Pablo and Choya-Foces, Carmen and Carregal-Romero, Susana and Ramos, Elena and Oliva, Tamara and Villa-Pi{~n}a, Tamara and Moreno, Laura and Izquierdo-{'A}lvarez, Alicia and Cabrera-Garc{'i}a, J Daniel and Cort{'e}s, Ana and Lechuga-Vieco, Ana Victoria and Jadiya, Pooja and Navarro, Elisa and Parada, Esther and Palomino-Antol{'i}n, Alejandra and Tello, Daniel and Ac{'i}n-P{'e}rez, Rebeca and Rodr{'i}guez-Aguilera, Juan Carlos and Navas, Pl{'a}cido and Cogolludo, Angel and L{'o}pez-Montero, Iv{'a}n and Mart{'i}nez-Del-Pozo, {'A}lvaro and Egea, Javier and L{'o}pez, Manuela G and Elrod, John W and Ruiz-Cabello, Jesus and Bogdanova, Anna and Enr{'i}quez, Jos{'e} Antonio and Mart{'i}nez-Ruiz, Antonio},
title = {{Na+ controls hypoxic signalling by the mitochondrial respiratory chain.}},
journal = {Nature},
year = {2020},
volume = {48},
number = {7828},
pages = {158--5},
month = jul,
publisher = {Nature Publishing Group},
affiliation = {Unidad de Investigaci{'o}n, Hospital Universitario Santa Cristina, Instituto de Investigaci{'o}n Sanitaria Princesa (IIS-IP), Madrid, Spain.},
doi = {10.1038/s41586-020-2551-y},
pmid = {32728214},
language = {English},
rating = {0},
date-added = {2020-10-13T14:28:50GMT},
date-modified = {2020-10-13T14:29:08GMT},
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.},
url = {http://www.nature.com/articles/s41586-020-2551-y},
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uri = {url{papers3://publication/doi/10.1038/s41586-020-2551-y}}
}