Hernansanz-Agustin 2019 bioRxiv

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Hernansanz-Agustín P, Choya-Foces C, Carregal-Romero S, Ramos E, Oliva T, Villa-Piña T, Moreno L, Izquierdo-Álvarez A, JCabrera-García JD, Cortés A, Lechuga-Vieco AV, Jadiya P, Navarro E, Parada E, Palomino-Antolín A, Tello D, Acín-Pérez R, Rodríguez-Aguilera JC, Navas P, Cogolludo A, López-Montero I, Martínez-del-Pozo A, Egea J, López MG, Elrod JW, Ruiz-Cabello J, Bogdanova A, Enríquez JA, Martínez-Ruiz A (2019) Mitochondrial Na+ import controls oxidative phosphorylation and hypoxic redox signalling. bioRxiv doi: https://doi.org/10.1101/385690.

» bioRxiv Open Access

Hernansanz-Agustin P, Choya-Foces C, Carregal-Romero S, Ramos E, Oliva T, Villa-Pina T, Moreno L, Izquierdo-Alvarez A, Cabrera-Garcia JD, Cortes A, Lechuga-Vieco AV, Jadiya P, Navarro E, Parada E, Palomino-Antolin A, Tello D, Acin-Perez R, Rodriguez-Aguilera JC, Navas P, Cogolludo A, Lopez-Montero I, Martinez-del-Pozo A, Egea J, Lopez MG, Elrod JW, Ruiz-Cabello J, Bogdanova A, Enríquez JA, Martinez-Ruiz A (2019) bioRxiv

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 damage, and both phenomena occur in hypoxia. 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 messenger, yet the role ascribed to Na+ is to serve as a mere mediator of membrane potential and collaborating in ion transport. 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 hypoxia 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


Bioblast editor: Plangger M


Labels: MiParea: Respiration 

Stress:Hypoxia  Organism: Rat, Bovines  Tissue;cell: Heart  Preparation: Isolated mitochondria 

Regulation: Ion;substrate transport 


HRR: Oxygraph-2k, O2k-Fluorometer 

2020-03, AmR