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CoQ imbalance drives reverse electron transport to disrupt liver metabolism

Author

Listed:
  • Renata L. S. Goncalves

    (Harvard T. H. Chan School of Public Health)

  • Zeqiu Branden Wang

    (Harvard T. H. Chan School of Public Health)

  • Jillian K. Riveros

    (Harvard T. H. Chan School of Public Health)

  • Güneş Parlakgül

    (Harvard T. H. Chan School of Public Health
    University of California Berkeley)

  • Karen E. Inouye

    (Harvard T. H. Chan School of Public Health)

  • Grace Yankun Lee

    (Harvard T. H. Chan School of Public Health)

  • Xiaorong Fu

    (University of Texas Southwestern Medical Center)

  • Jani Saksi

    (Harvard T. H. Chan School of Public Health)

  • Clement Rosique

    (Harvard T. H. Chan School of Public Health)

  • Sheng Tony Hui

    (Harvard T. H. Chan School of Public Health)

  • Mar Coll

    (Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CiberEHD)
    University of Barcelona)

  • Ana Paula Arruda

    (Harvard T. H. Chan School of Public Health
    University of California Berkeley)

  • Shawn C. Burgess

    (University of Texas Southwestern Medical Center)

  • Isabel Graupera

    (Harvard T. H. Chan School of Public Health
    Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CiberEHD)
    University of Barcelona)

  • Gökhan S. Hotamışlıgil

    (Harvard T. H. Chan School of Public Health
    Broad Institute of MIT and Harvard)

Abstract

Mitochondrial reactive oxygen species (mROS) are central to physiology1,2. Excess mROS production has been associated with several disease states2,3; however, the precise sources, regulation and mechanism of generation in vivo remain unclear, which limits translational efforts. Here we show that in obesity, hepatic coenzyme Q (CoQ) synthesis is impaired, which increases the CoQH2 to CoQ (CoQH2/CoQ) ratio and drives excessive mROS production through reverse electron transport (RET) from site IQ in complex I. Using multiple complementary genetic and pharmacological models in vivo, we demonstrate that RET is crucial for metabolic health. In patients with steatosis, the hepatic CoQ biosynthetic program is also suppressed, and the CoQH2/CoQ ratio positively correlates with disease severity. Our data identify a highly selective mechanism for pathological mROS production in obesity, which can be targeted to protect metabolic homeostasis.

Suggested Citation

  • Renata L. S. Goncalves & Zeqiu Branden Wang & Jillian K. Riveros & Güneş Parlakgül & Karen E. Inouye & Grace Yankun Lee & Xiaorong Fu & Jani Saksi & Clement Rosique & Sheng Tony Hui & Mar Coll & Ana P, 2025. "CoQ imbalance drives reverse electron transport to disrupt liver metabolism," Nature, Nature, vol. 643(8073), pages 1057-1065, July.
    • Handle: RePEc:nat:nature:v:643:y:2025:i:8073:d:10.1038_s41586-025-09072-1
    DOI: 10.1038/s41586-025-09072-1
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