biostudies-literatureHernansanz-Agustin PSwiss National Science FoundationNHLBI NIH HHSNINDS NIH HHS287-291https://www.ebi.ac.uk/biostudies/studies/S-EPMC7992277biostudies-literatureUnknown586(7828)All metazoans depend on the consumption of O₂ by the mitochondrial oxidative phosphorylation system (OXPHOS) to produce energy. In addition, the OXPHOS uses O₂ to produce reactive oxygen species that can drive cell adaptations^1-4, a phenomenon that occurs in hypoxia^4-8 and whose precise mechanism remains unknown. Ca²⁺ is the best known ion that acts as a second messenger⁹, yet the role ascribed to Na⁺ is to serve as a mere mediator of membrane potential¹⁰. Here we show that Na⁺ acts as a second messenger that regulates OXPHOS function and the production of reactive oxygen species by modulating the fluidity of the inner mitochondrial membrane. A conformational shift in mitochondrial complex I NatureNa⁺ controls hypoxic signalling by the mitochondrial respiratory chain.PMC7992277R01 HL123966124970R01 HL142271310030R01 HL136954RF1 NS121379Cortes AMartinez-Ruiz ACogolludo AEnriquez JAParada ELopez MGEgea JAcin-Perez RMartinez-Del-Pozo AIzquierdo-Alvarez ANavarro EVilla-Pina TCabrera-Garcia JDLopez-Montero ICarregal-Romero SRodriguez-Aguilera JCChoya-Foces CElrod JWTello DJadiya PLechuga-Vieco AVRuiz-Cabello JBogdanova AHernansanz-Agustin PMoreno LPalomino-Antolin AOliva TNavas PRamos EfalseNa⁺ controls hypoxic signalling by the mitochondrial respiratory chain.All metazoans depend on the consumption of O₂ by the mitochondrial oxidative phosphorylation system (OXPHOS) to produce energy. In addition, the OXPHOS uses O₂ to produce reactive oxygen species that can drive cell adaptations^1-4, a phenomenon that occurs in hypoxia^4-8 and whose precise mechanism remains unknown. Ca²⁺ is the best known ion that acts as a second messenger⁹, yet the role ascribed to Na⁺ is to serve as a mere mediator of membrane potential¹⁰. Here we show that Na⁺ acts as a second messenger that regulates OXPHOS function and the production of reactive oxygen species by modulating the fluidity of the inner mitochondrial membrane. A conformational shift in mitochondrial complex I 2020-01-01T00:00:00Z2020 Oct2026-05-02T11:26:54.066Z2025-04-05T17:16:03.366ZS-EPMC79922773272821410.1038/s41586-020-2551-y