Mitochondrial Na+ controls oxidative phosphorylation and hypoxic redox signalling

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Hernansanz Agustín, Pablo and Choya Foces, Carmen and Carregal Romero, Susana and Ramos, Elena and Oliva, Tamara and Villa Piña, Tamara and Moreno, Laura and Izquierdo Alvarez, Alicia and Cabrera Garcia, J.Daniel and Cortés, Ana and Lechuga Vieco, Ana Victoria and Jadiya, Pooja and Navarro, Elisa and Parada, Esther and Palomino Antolín, Alejandra and Tello, Daniel and Acín Pérez, Rebeca and Rodríguez Aguilera, Juan Carlos and Navas, Plácido and Cogolludo, Angel and López Montero, Iván and Martínez del Pozo, Álvaro and Egea, Javier and López, Manuela G. and Elrod, John W. and Ruiz Cabello, J. and Bogdanova, Anna and Enríquez, José Antonio and Martínez Ruiz, Antonio (2020) Mitochondrial Na+ controls oxidative phosphorylation and hypoxic redox signalling. Nature (London) . ISSN 0028-0836

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Official URL: https://www.nature.com/articles/s41586-020-2551-y



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.


Item Type:Article
Uncontrolled Keywords:NADH Dehydrogenase (Quinone) | Ubiquinones | Ubiquinol Cytochrome C Reductase
Subjects:Sciences > Chemistry > Molecular biology
Sciences > Chemistry > Biochemistry
ID Code:62260
Deposited On:24 Sep 2020 08:04
Last Modified:24 Sep 2020 08:32

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