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We acknowledge all CBMSO (Centre for Molecular Biology Severo Ochoa, CSIC-UAM) facilities and D. Abia from CBMSO-Bioinformatics Unit for help and advice. We are grateful to L. Civettini for assistance and technical discussions. Mutated ACAD9- and AOX-expressing fibroblasts were kindly gifted by M.A. Martin-Casanueva and J.A. Enriquez, respectively. This work was supported by grants from the Ministerio de Ciencia e Innovacion, Spain (PID2019-104241RB-I00 and PID2022-136738OB-I00, MCIN/AEI/10.13039/501100011033) and the Fundacion Ramon Areces, Spain. Principal investigator: L.F. B.S.A. is supported by a FPU predoctoral grant (FPU2022/00218) and G.A.-R. is supported by a Juan de la Cierva-Incorporacion postdoctoral grant (IJC2019-041482-I), awarded by the Ministerio de Universidades (MU) and the Ministerio de Ciencia e Innovacion (MC), respectively.

Analysis of institutional authors

Herrero Martin, Juan CruzAuthorMartin, Juan Cruz HerreroAuthorAnsa, Benat SalegiAuthorDominguez-Zorita, SoniaAuthorRodriguez-Pombo, PilarAuthorMiguez, David GAuthorCifuentes, AlejandroAuthorCuezva, Jose MAuthorFormentini, LauraCorresponding Author

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July 18, 2024
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Article
Hybrid Gold

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

Publicated to:Nature Metabolism. 6 (2): 209-+ - 2024-02-01 6(2), DOI: 10.1038/s42255-023-00956-y

Authors: Martin, Juan Cruz Herrero; Ansa, Benat Salegi; Alvarez-Rivera, Gerardo; Dominguez-Zorita, Sonia; Rodriguez-Pombo, Pilar; Perez, Belen; Calvo, Enrique; Miguez, David G; Cifuentes, Alejandro; Cuezva, Jose M; Formentini, Laura

Affiliations

CIBERER, ISCIII, Madrid, Spain - Author
CNIC Carlos III, Prote Unit, Madrid, Spain - Author
CSIC, Prote Unit, CNB, Madrid, Spain - Author
IdiPAZ, Madrid, Spain - Author
Inst Invest Hosp 12 Octubre I 12, Madrid, Spain - Author
Univ Autonoma Madrid UAM, CEDEM, Madrid, Spain - Author
Univ Autonoma Madrid UAM, CIAL, Lab Food, CSIC, Madrid, Spain - Author
Univ Autonoma Madrid UAM, Dept Biol Mol, Ctr Biol Mol Severo Ochoa CBMSO, CSIC, Madrid, Spain - Author
Univ Autonoma Madrid UAM, Dept Fis Mat Condensada, IFIMAC, Madrid, Spain - Author
Univ Autonoma Madrid UAM, Inst Univ Biol Mol IUBM, Madrid, Spain - Author
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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.

Keywords

Acid beta-oxidationAnimalsChaiComplex-iiiCytochrome-bElectron-transferElectron-transferring flavoproteinsFlavoprotein-ubiquinone oxidoreductaseH+-atp synthaseHomeostasisLipidsMiceMitochondrialMuscle, skeletalOxidative phosphorylationQ-cycleRos productionUbiquinone

Quality index

Bibliometric impact. Analysis of the contribution and dissemination channel

The work has been published in the journal Nature Metabolism due to its progression and the good impact it has achieved in recent years, according to the agency WoS (JCR), it has become a reference in its field. In the year of publication of the work, 2024 there are still no calculated indicators, but in 2023, it was in position 5/186, thus managing to position itself as a Q1 (Primer Cuartil), in the category Endocrinology & Metabolism. Notably, the journal is positioned above the 90th percentile.

Independientemente del impacto esperado determinado por el canal de difusión, es importante destacar el impacto real observado de la propia aportación.

Según las diferentes agencias de indexación, el número de citas acumuladas por esta publicación hasta la fecha 2025-08-02:

  • Google Scholar: 10
  • WoS: 10
  • Scopus: 10
  • Europe PMC: 7

Impact and social visibility

From the perspective of influence or social adoption, and based on metrics associated with mentions and interactions provided by agencies specializing in calculating the so-called "Alternative or Social Metrics," we can highlight as of 2025-08-02:

  • The use, from an academic perspective evidenced by the Altmetric agency indicator referring to aggregations made by the personal bibliographic manager Mendeley, gives us a total of: 29.
  • The use of this contribution in bookmarks, code forks, additions to favorite lists for recurrent reading, as well as general views, indicates that someone is using the publication as a basis for their current work. This may be a notable indicator of future more formal and academic citations. This claim is supported by the result of the "Capture" indicator, which yields a total of: 33 (PlumX).

With a more dissemination-oriented intent and targeting more general audiences, we can observe other more global scores such as:

  • The Total Score from Altmetric: 56.2.
  • The number of mentions on the social network X (formerly Twitter): 99 (Altmetric).

It is essential to present evidence supporting full alignment with institutional principles and guidelines on Open Science and the Conservation and Dissemination of Intellectual Heritage. A clear example of this is:

  • The work has been submitted to a journal whose editorial policy allows open Open Access publication.
  • Assignment of a Handle/URN as an identifier within the deposit in the Institutional Repository: https://repositorio.uam.es/handle/10486/711851

Leadership analysis of institutional authors

There is a significant leadership presence as some of the institution’s authors appear as the first or last signer, detailed as follows: First Author (PEREZ GONZALEZ, MARIA BELEN) and Last Author (FORMENTINI ., LAURA).

the author responsible for correspondence tasks has been FORMENTINI ., LAURA.