The unexpected role of Na+ in mitochondrial bioenergetics, ROS production and homeostasis

In the last few years, mitochondrial Na+ has emerged as an important player for cellular adaptation and bioenergetics. Previously, the role of Na+ was confined to the co-maintenance of plasma membrane potential. Now, the role of Na+, particularly in the mitochondria, has expanded after its discovery as a second messenger. During acute hypoxia, Na+ enters in the mitochondrial matrix, interacts with phospholipids, regulating the inner mitochondrial membrane (IMM) fluidity and ROS production by the mitochondrial electron transport chain (mETC). In addition, it ahs been recently shown that, in normal conditions, Na+ also have deep implications in bioenergetics. It forms a gradient across the IMM which accounts for half of the ΔΨmt. This gradient is built up by the activity of the mitochondrial Na+-specific Na+/H+ exchanger (mNHE), which partially dissipates the H+ gradient (ΔpH) to generate the Na+ gradient (ΔNa+). Interestingly, the molecular identity of this exchanger is complex I (CI). These roles of mitochondrial Na+ allow the control over mitochondrial Ca2+ and Mg2+ content through the activity of NCLX and SLC41A3, respectively, and open a novel relationship with physiology and disease. Overall, this review focus on how mitochondrial Na+ regulates bioenergetics, mitochondrial ion handling and ROS levels, as well as its consequences for cell life and death.