1. Ubiquinone deficiency drives reverse electron transport to disrupt hepatic metabolic homeostasis in obesity
- Author
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Renata L.S. Goncalves, Zeqiu Branden Wang, Karen E. Inouye, Grace Yankun Lee, Xiaorong Fu, Jani Saksi, Clement Rosique, Gunes Parlakgul, Ana Paula Arruda, Sheng Tony Hui, Mar Coll Loperena, Shawn C. Burgess, Isabel Graupera, and Gökhan S. Hotamisligil
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Article - Abstract
Mitochondrial reactive oxygen species (mROS) are central to physiology. While excess mROS production has been associated with several disease states, its precise sources, regulation, and mechanism of generationin vivoremain unknown, limiting translational efforts. Here we show that in obesity, hepatic ubiquinone (Q) synthesis is impaired, which raises the QH2/Q ratio, driving excessive mROS production via reverse electron transport (RET) from site IQin complex I. Using multiple complementary genetic and pharmacological modelsin vivowe demonstrated that RET is critical for metabolic health. In patients with steatosis, the hepatic Q biosynthetic program is also suppressed, and the QH2/Q 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.
- Published
- 2023
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