辅酶Q失衡驱动逆向电子传递以扰乱肝脏代谢。

CoQ imbalance drives reverse electron transport to disrupt liver metabolism.

作者信息

Goncalves Renata L S, Wang Zeqiu Branden, Riveros Jillian K, Parlakgül Güneş, 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, Hotamışlıgil Gökhan S

机构信息

Department of Molecular Metabolism, Harvard T. H. Chan School of Public Health, Boston, MA, USA.

Department of Nutritional Sciences and Toxicology, University of California Berkeley, Berkeley, CA, USA.

出版信息

Nature. 2025 May 28. doi: 10.1038/s41586-025-09072-1.

DOI:10.1038/s41586-025-09072-1

PMID:40437093

Abstract

Mitochondrial reactive oxygen species (mROS) are central to physiology. Excess mROS production has been associated with several disease states; 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 CoQH to CoQ (CoQH/CoQ) ratio and drives excessive mROS production through reverse electron transport (RET) from site I 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 CoQH/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.

摘要

线粒体活性氧（mROS）在生理学中至关重要。mROS产生过多与多种疾病状态相关；然而，其在体内的确切来源、调控及生成机制仍不清楚，这限制了相关转化研究工作。在此我们表明，在肥胖状态下，肝脏辅酶Q（CoQ）合成受损，这增加了CoQH与CoQ（CoQH/CoQ）的比率，并通过复合物I中位点I的逆向电子传递（RET）驱动mROS过度产生。利用多种体内互补的遗传和药理学模型，我们证明RET对代谢健康至关重要。在脂肪变性患者中，肝脏CoQ生物合成程序也受到抑制，且CoQH/CoQ比率与疾病严重程度呈正相关。我们的数据确定了肥胖中病理性mROS产生的一种高度选择性机制，该机制可作为靶点来保护代谢稳态。