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

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.

Bibliographic Details

Main Authors:	Herrero Martín, Juan Cruz, Salegi Ansa, Beñat, Álvarez-Rivera, Gerardo, Domínguez-Zorita, Sonia, Rodríguez-Pombo, Pilar, Pérez, Belén, Calvo, Enrique, Paradela, Alberto, Miguez, David G., Cifuentes, Alejandro, Cuezva, José M., Formentini, Laura
Other Authors:	Ministerio de Ciencia, Innovación y Universidades (España)
Format:	artículo biblioteca
Language:	English
Published:	Springer Nature 2024-02
Online Access:	http://hdl.handle.net/10261/358770 https://api.elsevier.com/content/abstract/scopus_id/85182633051
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