Na controls hypoxic signalling by the mitochondrial respiratory chain.

All metazoans depend on the consumption of O by the mitochondrial oxidative phosphorylation system (OXPHOS) to produce energy. In addition, the OXPHOS uses O to produce reactive oxygen species that can drive cell adaptations, a phenomenon that occurs in hypoxia and whose precise mechanism remains unknown. Ca is the best known ion that acts as a second messenger, yet the role ascribed to Na is to serve as a mere mediator of membrane potential. 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 drives acidification of the matrix and the release of free Ca from calcium phosphate (CaP) precipitates. The concomitant activation of the mitochondrial Na/Ca 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 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.