An ETFDH-driven metabolon supports OXPHOS efficiency in skeletal muscle by regulating coenzyme Q homeostasis
Juan Cruz Herrero Martín, Beñat Salegi Ansa, Gerardo Álvarez‐Rivera, Sonia Domínguez-Zorita, Pilar Rodríguez‐Pombo, Belén Pérez, Enrique Calvo, Alberto Paradela, David G. Míguez, Alejandro Cifuentes, José M. Cuezva, Laura Formentini
Abstract
Abstract Coenzyme 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 (QH 2 ); however, in eukaryotes, only oxidative phosphorylation (OXPHOS) complex III (CIII) oxidizes QH 2 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 QH 2 -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.