Goncalves Renata L S, Wang Zeqiu Branden, Inouye Karen E, Lee Grace Yankun, Fu Xiaorong, Saksi Jani, Rosique Clement, Parlakgul Gunes, Arruda Ana Paula, Hui Sheng Tony, Loperena Mar Coll, Burgess Shawn C, Graupera Isabel, Hotamisligil Gökhan S
bioRxiv. 2023 Feb 22:2023.02.21.528863. doi: 10.1101/2023.02.21.528863.
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 generation remain unknown, limiting translational efforts. Here we show that in obesity, hepatic ubiquinone (Q) synthesis is impaired, which raises the QH /Q ratio, driving excessive mROS production via reverse electron transport (RET) from site I in complex I. Using multiple complementary genetic and pharmacological models we demonstrated that RET is critical for metabolic health. In patients with steatosis, the hepatic Q biosynthetic program is also suppressed, and the QH /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.
线粒体活性氧（mROS）在生理学中至关重要。虽然过量的mROS产生与多种疾病状态相关，但其确切来源、调节和产生机制仍不清楚，这限制了转化研究的进展。在这里，我们表明在肥胖状态下，肝脏泛醌（Q）合成受损，这会提高QH₂/Q比值，通过复合体I中位点I的逆向电子传递（RET）驱动过量的mROS产生。使用多种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Q生物合成程序也受到抑制，且QH₂/Q比值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。
