An ETFDH-driven metabolon supports OXPHOS efficiency in skeletal muscle by regulating coenzyme Q homeostasis

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2024年1月19日

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Juan Cruz Herrero Martín,
Beñat Salegi Ansa,
Gerardo Álvarez-Rivera,
Sonia Domínguez-Zorita,
Pilar Rodríguez-Pombo,
Belén Pérez,
Enrique Calvo,
Alberto Paradela,
David G. Miguez,
Alejandro Cifuentes,
José M. Cuezva,
Laura Formentini

摘要

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 (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.