RT Journal Article
T1 Mitochondrial Na+ controls oxidative phosphorylation and hypoxic redox signalling
A1 Hernansanz Agustín, Pablo
A1 Choya Foces, Carmen
A1 Carregal Romero, Susana
A1 Ramos, Elena
A1 Oliva, Tamara
A1 Villa Piña, Tamara
A1 Moreno, Laura
A1 Izquierdo Alvarez, Alicia
A1 Cabrera Garcia, J.Daniel
A1 Cortés, Ana
A1 Lechuga Vieco, Ana Victoria
A1 Jadiya, Pooja
A1 Navarro, Elisa
A1 Parada, Esther
A1 Palomino Antolín, Alejandra
A1 Tello, Daniel
A1 Acín Pérez, Rebeca
A1 Rodríguez Aguilera, Juan Carlos
A1 Navas, Plácido
A1 Cogolludo, Angel
A1 López Montero, Iván
A1 Martínez del Pozo, Álvaro
A1 Egea, Javier
A1 López, Manuela G.
A1 Elrod, John W.
A1 Ruiz Cabello, J.
A1 Bogdanova, Anna
A1 Enríquez, José Antonio
A1 Martínez Ruiz, Antonio
AB 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.
PB Nature Research
SN 0028-0836
YR 2020
FD 2020-07-29
LK https://hdl.handle.net/20.500.14352/6576
UL https://hdl.handle.net/20.500.14352/6576
LA spa
NO Unión Europea. FP7
NO Ministerio de Economía y Competitividad (MINECO)/FEDER
NO Comunidad de Madrid
NO Centro de Excelencia Severo Ochoa
NO Unidad de Excelencia Maria de Maeztu
DS Docta Complutense
RD 2 sept 2024