Hernansanz-Agustín, PabloMorales-Vidal, CarmenCalvo, EnriqueNatale, PaoloMartí-Mateos, YolandaJaroszewicz, Sara NataliaCabrera-Alarcón, José LuisAcín-Pérez, RebecaLópez-Montero, IvánVázquez, JesúsEnríquez, José Antonio2024-12-042024-12-042024-11-14Cell. 2024 Nov 14;187(23):6599-6613.e21.https://hdl.handle.net/20.500.12105/25849This study was supported by competitive grants from the Ministerio de Ciencia e Innovacio´ n (MCIN) RTI2018-099357-B-I00, CIBERFES (CB16/10/00282), Human Frontier Science Program (grant RGP0016/2018), and Leducq Transatlantic Networks (17CVD04) to J.A.E. P.H.-A. is supported by a JdC IJC2020-042679-I, and Y.M.-M. is supported by an FPI-SO fellowship PRE2018-083478. The CNIC is supported by the Instituto de Salud Carlos III (ISCIII), the Ministerio de Ciencia, Innovacio´ n y Universidades (MICIU), and the Pro CNIC Foundation, and is a Severo Ochoa Center of Excellence (grant CEX2020-001041-S funded by MICIU/AEI/10.13039/501100011033). I.L.-M. acknowledges financial support through the TECNOLOGI´AS 2018 program funded by the Regional Government of Madrid (grant S2018/BAA-4403 SINOXPHOS-CM).Eukaryotic cell function and survival rely on the use of a mitochondrial H electrochemical gradient (Δp), which is composed of an inner mitochondrial membrane (IMM) potential (ΔΨmt) and a pH gradient (ΔpH). So far, ΔΨmt has been assumed to be composed exclusively of H. Here, using a rainbow of mitochondrial and nuclear genetic models, we have discovered that a Na gradient equates with the H gradient and controls half of ΔΨmt in coupled-respiring mammalian mitochondria. This parallelism is controlled by the activity of the long-sought Na-specific Na/H exchanger (mNHE), which we have identified as the P-module of complex I (CI). Deregulation of this mNHE function, without affecting the canonical enzymatic activity or the assembly of CI, occurs in Leber's hereditary optic neuropathy (LHON), which has profound consequences in ΔΨmt and mitochondrial Ca homeostasis and explains the previously unknown molecular pathogenesis of this neurodegenerative disease.engVoRhttp://creativecommons.org/licenses/by-nc-nd/4.0/LHONNa(+) gradientcomplex Imitochondrial Na(+)/H(+) antiporterΔΨmtAttribution-NonCommercial-NoDerivatives 4.0 International39303716187236599-6613Cellopen access