Mitochondrial Na+ controls oxidative phosphorylation and hypoxic redox signalling
dc.contributor.author | Hernansanz Agustín, Pablo | |
dc.contributor.author | Choya Foces, Carmen | |
dc.contributor.author | Carregal Romero, Susana | |
dc.contributor.author | Ramos, Elena | |
dc.contributor.author | Oliva, Tamara | |
dc.contributor.author | Villa Piña, Tamara | |
dc.contributor.author | Moreno, Laura | |
dc.contributor.author | Izquierdo Alvarez, Alicia | |
dc.contributor.author | Cabrera Garcia, J.Daniel | |
dc.contributor.author | Cortés, Ana | |
dc.contributor.author | Lechuga Vieco, Ana Victoria | |
dc.contributor.author | Jadiya, Pooja | |
dc.contributor.author | Navarro, Elisa | |
dc.contributor.author | Parada, Esther | |
dc.contributor.author | Palomino Antolín, Alejandra | |
dc.contributor.author | Tello, Daniel | |
dc.contributor.author | Acín Pérez, Rebeca | |
dc.contributor.author | Rodríguez Aguilera, Juan Carlos | |
dc.contributor.author | Navas, Plácido | |
dc.contributor.author | Cogolludo, Angel | |
dc.contributor.author | López Montero, Iván | |
dc.contributor.author | Martínez del Pozo, Álvaro | |
dc.contributor.author | Egea, Javier | |
dc.contributor.author | López, Manuela G. | |
dc.contributor.author | Elrod, John W. | |
dc.contributor.author | Ruiz Cabello, J. | |
dc.contributor.author | Bogdanova, Anna | |
dc.contributor.author | Enríquez, José Antonio | |
dc.contributor.author | Martínez Ruiz, Antonio | |
dc.date.accessioned | 2023-06-16T15:23:57Z | |
dc.date.available | 2023-06-16T15:23:57Z | |
dc.date.issued | 2020-07-29 | |
dc.description.abstract | All metazoans depend on O2 delivery and consumption by the mitochondrial oxidative phosphorylation (OXPHOS) system to produce energy. A decrease in O2 availability (hypoxia) leads to profound metabolic rewiring. In addition, OXPHOS uses O2 to produce reactive oxygen species (ROS) that can drive cell adaptations through redox signalling, but also trigger cell damage1–4, and both phenomena occur in hypoxia4–8. However, the precise mechanism by which acute hypoxia triggers mitochondrial ROS production is still unknown. Ca2+ is one of the best known examples of an ion acting as a second messenger9, yet the role ascribed to Na+ is to serve as a mere mediator of membrane potential and collaborating in ion transport10. Here we show that Na+ acts as a second messenger regulating OXPHOS function and ROS production by modulating fluidity of the inner mitochondrial membrane (IMM). We found that a conformational shift in mitochondrial complex I during acute hypoxia11 drives the acidification of the matrix and solubilization of calcium phosphate precipitates. The concomitant increase in matrix free-Ca2+ activates the mitochondrial Na+/Ca2+ exchanger (NCLX), which imports Na+ into the matrix. Na+ interacts with phospholipids reducing IMM fluidity and mobility of free ubiquinone between complex II and complex III, but not inside supercomplexes. As a consequence, superoxide is produced at complex III, generating a redox signal. Inhibition of mitochondrial Na+ import through NCLX is sufficient to block this pathway, preventing adaptation to hypoxia. These results reveal that Na+ import into the mitochondrial matrix controls OXPHOS function and redox signalling through an unexpected interaction with phospholipids, with profound consequences in cellular metabolism. | |
dc.description.department | Depto. de Bioquímica y Biología Molecular | |
dc.description.faculty | Fac. de Ciencias Químicas | |
dc.description.refereed | TRUE | |
dc.description.sponsorship | Unión Europea. FP7 | |
dc.description.sponsorship | Ministerio de Economía y Competitividad (MINECO)/FEDER | |
dc.description.sponsorship | Comunidad de Madrid | |
dc.description.sponsorship | Centro de Excelencia Severo Ochoa | |
dc.description.sponsorship | Unidad de Excelencia Maria de Maeztu | |
dc.description.status | pub | |
dc.eprint.id | https://eprints.ucm.es/id/eprint/62260 | |
dc.identifier.doi | 10.1038/s41586-020-2551-y | |
dc.identifier.issn | 0028-0836 | |
dc.identifier.officialurl | https://www.nature.com/articles/s41586-020-2551-y | |
dc.identifier.uri | https://hdl.handle.net/20.500.14352/6576 | |
dc.journal.title | Nature (London) | |
dc.language.iso | spa | |
dc.publisher | Nature Research | |
dc.relation.projectID | MEET (317433); ROLROS (304217) | |
dc.relation.projectID | (CSD2007-00020; CP07/00143, PS09/00101, PI12/00875, PI15/00107; RTI2018-094203-B-I00; CP12/03304 and PI15/01100; SAF2016-77222-R, SAF2015-65633-R; SAF2013-32223, SAF2017-84494-2-R) | |
dc.relation.projectID | (B2017/BMD-3727) | |
dc.relation.projectID | SEV2015-0505 | |
dc.relation.projectID | MDM-2017-0720 | |
dc.rights.accessRights | open access | |
dc.subject.cdu | 577.1 | |
dc.subject.keyword | NADH Dehydrogenase (Quinone) | |
dc.subject.keyword | Ubiquinones | |
dc.subject.keyword | Ubiquinol Cytochrome C Reductase | |
dc.subject.ucm | Biología molecular (Química) | |
dc.subject.ucm | Bioquímica (Química) | |
dc.title | Mitochondrial Na+ controls oxidative phosphorylation and hypoxic redox signalling | |
dc.type | journal article | |
dspace.entity.type | Publication | |
relation.isAuthorOfPublication | f695bacc-278b-4155-93dc-eaa4b0ec28fe | |
relation.isAuthorOfPublication | eec0b303-34c9-47dd-9ec6-704b6c6c7acd | |
relation.isAuthorOfPublication.latestForDiscovery | f695bacc-278b-4155-93dc-eaa4b0ec28fe |
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