CoQ imbalance drives reverse electron transport to disrupt liver metabolism

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 Paula Arruda, Shawn C. Burgess, Isabel Graupera and Gökhan S. Hotamışlıgil ()
Additional contact information
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
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)
Ana Paula Arruda: Harvard T. H. Chan School of Public Health
Shawn C. Burgess: University of Texas Southwestern Medical Center
Isabel Graupera: Harvard T. H. Chan School of Public Health
Gökhan S. Hotamışlıgil: Harvard T. H. Chan School of Public Health

Nature, 2025, vol. 643, issue 8073, 1057-1065

Abstract: 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.

Date: 2025
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DOI: 10.1038/s41586-025-09072-1

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