Mitochondrial Na+ controls oxidative phosphorylation and hypoxic redox signalling

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dc.contributor.authorHernansanz Agustín, Pablo
dc.contributor.authorChoya Foces, Carmen
dc.contributor.authorCarregal Romero, Susana
dc.contributor.authorRamos, Elena
dc.contributor.authorOliva, Tamara
dc.contributor.authorVilla Piña, Tamara
dc.contributor.authorMoreno, Laura
dc.contributor.authorIzquierdo Alvarez, Alicia
dc.contributor.authorCabrera Garcia, J.Daniel
dc.contributor.authorCortés, Ana
dc.contributor.authorLechuga Vieco, Ana Victoria
dc.contributor.authorJadiya, Pooja
dc.contributor.authorNavarro, Elisa
dc.contributor.authorParada, Esther
dc.contributor.authorPalomino Antolín, Alejandra
dc.contributor.authorTello, Daniel
dc.contributor.authorAcín Pérez, Rebeca
dc.contributor.authorRodríguez Aguilera, Juan Carlos
dc.contributor.authorNavas, Plácido
dc.contributor.authorCogolludo, Angel
dc.contributor.authorLópez Montero, Iván
dc.contributor.authorMartínez del Pozo, Álvaro
dc.contributor.authorEgea, Javier
dc.contributor.authorLópez, Manuela G.
dc.contributor.authorElrod, John W.
dc.contributor.authorRuiz Cabello, J.
dc.contributor.authorBogdanova, Anna
dc.contributor.authorEnríquez, José Antonio
dc.contributor.authorMartínez Ruiz, Antonio
dc.date.accessioned2023-06-16T15:23:57Z
dc.date.available2023-06-16T15:23:57Z
dc.date.issued2020-07-29
dc.description.abstractAll 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.departmentDepto. de Bioquímica y Biología Molecular
dc.description.facultyFac. de Ciencias Químicas
dc.description.refereedTRUE
dc.description.sponsorshipUnión Europea. FP7
dc.description.sponsorshipMinisterio de Economía y Competitividad (MINECO)/FEDER
dc.description.sponsorshipComunidad de Madrid
dc.description.sponsorshipCentro de Excelencia Severo Ochoa
dc.description.sponsorshipUnidad de Excelencia Maria de Maeztu
dc.description.statuspub
dc.eprint.idhttps://eprints.ucm.es/id/eprint/62260
dc.identifier.doi10.1038/s41586-020-2551-y
dc.identifier.issn0028-0836
dc.identifier.officialurlhttps://www.nature.com/articles/s41586-020-2551-y
dc.identifier.urihttps://hdl.handle.net/20.500.14352/6576
dc.journal.titleNature (London)
dc.language.isospa
dc.publisherNature Research
dc.relation.projectIDMEET (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.projectIDSEV2015-0505
dc.relation.projectIDMDM-2017-0720
dc.rights.accessRightsopen access
dc.subject.cdu577.1
dc.subject.keywordNADH Dehydrogenase (Quinone)
dc.subject.keywordUbiquinones
dc.subject.keywordUbiquinol Cytochrome C Reductase
dc.subject.ucmBiología molecular (Química)
dc.subject.ucmBioquímica (Química)
dc.titleMitochondrial Na+ controls oxidative phosphorylation and hypoxic redox signalling
dc.typejournal article
dspace.entity.typePublication
relation.isAuthorOfPublicationf695bacc-278b-4155-93dc-eaa4b0ec28fe
relation.isAuthorOfPublicationeec0b303-34c9-47dd-9ec6-704b6c6c7acd
relation.isAuthorOfPublication.latestForDiscoveryf695bacc-278b-4155-93dc-eaa4b0ec28fe
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