Sodium in Mitochondrial Redox Signaling

Background: Mitochondrial Na+ has been discovered as a new second messenger regulating inner mitochondrial membrane (IMM) fluidity and reactive oxygen species (ROS) production by complex III (CIII). However, the roles of mitochondrial Na+ in mitochondrial redox signaling go beyond what was initially expected.Significance: In this review, we systematize the current knowledge on mitochondrial Na+ homeostasis and its implications on different modes of ROS production by mitochondria. Na+ behaves as a positive modulator of forward mitochondrial ROS production either by complex III (CIII) or by decreasing antioxidant capacity of mitochondria and as a potential negative modulator of reverse electron transfer (RET) by complex I (CI). Such duality depends on the bioenergetic status, cation and redox contexts, and can either lead to potential adaptations or cell death.Future Directions: Direct Na+ interaction with phospholipids, proven in the IMM, allows us to hypothesize its potential role in the existence and function of lipid rafts in other biological membranes regarding redox homeostasis, as well as the potential role of other monovalent cations in membrane biology. Thus, we provide the reader an update on the emerging field of mitochondrial Na+ homeostasis and its relationship with mitochondrial redox signaling.