Herrero Martín, Juan CruzSalegi Ansa, BeñatÁlvarez-Rivera, GerardoDomínguez-Zorita, SoniaRodríguez-Pombo, PilarPérez, BelénCalvo, EnriqueParadela, AlbertoMiguez, David GCifuentes, AlejandroCuezva, José MFormentini, Laura2024-07-032024-07-032024-02Nat Metab. 2024 Feb;6(2):209-225.http://hdl.handle.net/20.500.12105/20032Coenzyme Q (Q) is a key lipid electron transporter, but several aspects of its biosynthesis and redox homeostasis remain undefined. Various flavoproteins reduce ubiquinone (oxidized form of Q) to ubiquinol (QH2); however, in eukaryotes, only oxidative phosphorylation (OXPHOS) complex III (CIII) oxidizes QH2 to Q. The mechanism of action of CIII is still debated. Herein, we show that the Q reductase electron-transfer flavoprotein dehydrogenase (ETFDH) is essential for CIII activity in skeletal muscle. We identify a complex (comprising ETFDH, CIII and the Q-biosynthesis regulator COQ2) that directs electrons from lipid substrates to the respiratory chain, thereby reducing electron leaks and reactive oxygen species production. This metabolon maintains total Q levels, minimizes QH2-reductive stress and improves OXPHOS efficiency. Muscle-specific Etfdh-/- mice develop myopathy due to CIII dysfunction, indicating that ETFDH is a required OXPHOS component and a potential therapeutic target for mitochondrial redox medicine.engVoRhttp://creativecommons.org/licenses/by/4.0/Electron-Transferring FlavoproteinsOxidative PhosphorylationUbiquinoneAnimalsMiceHomeostasisLipidsMuscle, SkeletalAtribución 4.0 Internacional382431316220910.1038/s42255-023-00956-y2522-5812Nature metabolismopen access