Na+/H+ antiporter activity by respiratory complex I controls mitochondrial membrane potential and is impaired in LHON disease

The mitochondrial electron transport chain (mETC) converts the energy of substrate oxidation into a H+ electrochemical gradient ({Delta}p), which is composed by an inner mitochondrial membrane (IMM) potential ({Delta}{Psi}mt) and a pH gradient ({Delta}pH). So far, {Delta}{Psi}mt has been assumed to be composed exclusively by H+. Mitochondrial Ca2+ and Na+ homeostasis, which are essential for cellular function, are controlled by exchangers and antiporters in the inner mitochondrial membrane (IMM). In the last few years, some of them have been identified, except for the Na+-specific mitochondrial Na+/H+ exchanger (mNHE). Here, using a rainbow of mitochondrial and nuclear genetic models, we have identified the P-module of complex I (CI) as the major mNHE. In turn, its activity creates a Na+ gradient across the IMM, parallel to {Delta}pH, which accounts for half of the {Delta}{Psi}mt in coupled respiring mitochondria. We have also found that a deregulation of this mNHE function in CI, without affecting its enzymatic activity, occurs in Leber hereditary optic neuropathy (LHON), which has profound consequences in {Delta}{Psi}mt and mitochondrial Ca2+ homeostasis and explains the previously unknown molecular pathogenesis of this neurodegenerative disease.