Mitochondrial Na+ import controls oxidative phosphorylation and hypoxic redox signaling

Reactive oxygen species (ROS) generated by mitochondria in acute hypoxia are a well-known example of mitochondria-derived signals that can drive cell adaptations. However, the precise mechanism by which they are produced is still unknown. Mitochondrial Ca 2 + movements have been considered direct effectors in cell signaling; but the role ascribed so far to mitochondrial Na + is to serve as a mere mediator to equilibrate membrane potential. Here we show that the mitochondrial Na + /Ca 2 + exchanger (NCLX) is activated by the mitochondrial complex I conformational shift induced by hypoxia. Na + imported into the matrix reduces the fluidity of the mitochondrial inner membrane and the mobility of free ubiquinone, decreasing electron transfer between specifically complexes II-III, and not between complexes I-III. The reduction in CoQ mobility alters the Q cycle and increases superoxide production at complex III. Inhibition of mitochondrial Na + import through NCLX is sufficient to block this pathway, preventing hypoxia adaptation and injury in ex vivo and in vivo models. These results underscore a new role for mitochondrial Na + in controlling OXPHOS function and mitochondrial redox signals and introduce a new therapeutic potential for NCLX inhibition.