Na(+) controls hypoxic signalling by the mitochondrial respiratory chain
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Abstract
All metazoans depend on the consumption of O 2 by the mitochondrial oxidative phosphorylation system (OXPHOS) to produce energy. In addition, the OXPHOS uses O 2 to produce reactive oxygen species that can drive cell adaptations 1-4, a phenomenon that occurs in hypoxia 4-8 and whose precise mechanism remains unknown. Ca 2+ is the best known ion that acts as a second messenger 9, yet the role ascribed to Na+ is to serve as a mere mediator of membrane potential 10. 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 hypoxia 11 drives acidification of the matrix and the release of free Ca 2+ from calcium phosphate (CaP) precipitates. The concomitant activation of the mitochondrial Na+/Ca 2+ 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+/Ca 2+ 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.
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From intact mitochondria, matrix mtROS cannot reach the cytosol or other compartments.
“Moreover, from intact mitochondria matrix mtROS cannot reach the cytosol or other compartments [38,122,127,129,131,310].”
From Functions of ROS in Macrophages and Antimicrobial Immunity (2021) · cites this paper as [122]
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- Authors
- Hernansanz-Agustín, P., Choya-Foces, C., Carregal-Romero, S., Ramos, E., Oliva, T., Villa-Piña, T., Moreno, L., Izquierdo-Álvarez, A., Cabrera-García, J. D., Cortés, A., Lechuga-Vieco, A. V., Jadiya, P., Navarro, E., Parada, E., Palomino-Antolín, A., Tello, D., Acín-Pérez, R., Rodríguez-Aguilera, J. C., Navas, P., Cogolludo, Á., López-Montero, I., Martínez-del-Pozo, Á., Egea, J., López, M. G., Elrod, J. W., Ruíz-Cabello, J., Bogdanova, A., Enríquez, J. A., & Martínez-Ruiz, A.
- Affiliations
- Hospital Universitario Santa Cristina (ES)
- Hospital Universitario de La Princesa (ES)
- Universidad Complutense de Madrid (ES)
- Consejo Superior de Investigaciones Científicas (ES)
- Temple University (US)
- Instituto de Investigación Sanitaria del Hospital Universitario de La Princesa (ES)
- University of Zurich (CH)
- ORCID
- Venue
- Nature
- Published
- 2020-07-29
- Volume
- 586
- Issue
- 7828
- Pages
- 287-291
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- PMC
- PMC7992277
- OpenAlex
- W3045576138
- Cited by
- 238
- References
- 60
- Citations by year
- 2026: 25 · 2025: 39 · 2024: 40 · 2023: 35 · 2022: 40 · 2021: 49 · 2020: 9 · 2019: 1
- FWCI
- 10.78
- Type
- journal article
- Language
- en
- Open access
- green
- doi.org
- Licence
- Locations
- Nature (publishedVersion)
- bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Library Open Repository (Universidad Complutense Madrid) (submittedVersion, other-oa)
- RePEc: Research Papers in Economics (submittedVersion)
- DIGITAL.CSIC (Spanish National Research Council (CSIC)) (submittedVersion)
- Zurich Open Repository and Archive (University of Zurich) (submittedVersion)
- Funders
- National Science Foundation
- Fundación BBVA
- Comunidad de Madrid (B2017, B2017/BMD3727, SEV-2015-0505)
- European Commission (317433, SEV-2015-0505, 304217, MDM-2017-0720, PI12/00875, PS09/00101)
- Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung (00020, 124970, 310030_124970/1, 310030)
- Eusko Jaurlaritza (MDM-2017-0720, KK-2019/bmG19)
- Universidad Autónoma de Madrid
- Ben-Gurion University of the Negev
- Banco Bilbao Vizcaya Argentaria
- Centro Nacional de Investigaciones Cardiovasculares (SEV‐2015‐0505)
- Fundación Domingo Martínez
- Medical Research Council
- Instituto de Salud Carlos III (PI12/00875, MDM-2017-0720, SEV-2015-0505, PI15/00107, CSD2007-00020, I3SNS, PI15/01100, PS09/00101)
- European Regional Development Fund (PI15/00107, SAF2017, MDM-2017-0720, SEV-2015-0505, SAF2015-65633-R, RTI2018)
- National Heart, Lung, and Blood Institute (R01HL123966, R01HL136954, R01HL142271)
- National Institute of Neurological Disorders and Stroke (RF1NS121379)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Mitochondrial Function and Pathology
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Redox biology and oxidative stress
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Hypoxia, and Metabolism
- Keywords
- sodium ions, hypoxia, mitochondrial respiratory chain, oxidative phosphorylation, reactive oxygen species, superoxide, mitochondrial complex III, mitochondrial complex I, phospholipids, Na+/Ca2+ exchanger, calcium phosphate precipitates, redox signaling, second messengers
- MeSH terms
- Animals, Hypoxia, Breast Neoplasms, Calcium Phosphates, Electron Transport, Humans, Male, Membrane Fluidity, Mice, Inbred C57BL, Mitochondria, Oxidative Phosphorylation, Chemical Precipitation, Sodium, Second Messenger Systems, Rats, Wistar, Reactive Oxygen Species, Sodium-Calcium Exchanger, Mitochondrial Proteins, Cell Line, Tumor, Mitochondrial Membranes, Rats
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