CoQ imbalance drives reverse electron transport to disrupt liver metabolism

• 成果类型: Article
• 署名作者: Goncalves, Renata L. S.; Wang, Zeqiu Branden; Riveros, Jillian K.; Parlakgul, Gunes; Inouye, Karen E.; Lee, Grace Yankun; Fu, Xiaorong; Saksi, Jani; Rosique, Clement; Hui, Sheng Tony; Coll, Mar; Arruda, Ana Paula; Burgess, Shawn C.; Graupera, Isabel; Hotamisligil, Goekhan S.
• 署名单位: Harvard University; Harvard T.H. Chan School of Public Health; University of Texas System; University of Texas Southwestern Medical Center; CIBER - Centro de Investigacion Biomedica en Red; CIBEREHD; University of Barcelona; Hospital Clinic de Barcelona; Harvard University; Massachusetts Institute of Technology (MIT); Broad Institute; University of California System; University of California Berkeley
• 刊物名称: Nature
• ISSN/ISSBN: 0028-2910
• DOI: 10.1038/s41586-025-09072-1
• 发表日期: 2025-07-24
• 关键词: mitochondrial complex i; insulin-resistance; superoxide-production; vitamin-e; generation; h2o2; hepatocytes; peroxide; disease; cell

摘要

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.