Mitochondrial reactive oxygen species (mROS) are central to physiology^1,2. Excess mROS production has been associated with several disease states^2,3; 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 I_Q 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.

线粒体活性氧 （mROS） 是生理学的核心 ^1,2。过量的 mROS 产生与多种疾病状态有关 ^2,3;然而，体内产生的确切来源、调节和机制仍不清楚，这限制了转化工作。在这里，我们表明在肥胖中，肝脏辅酶 Q （CoQ） 合成受损，这增加了 CoQH₂ 与 CoQ （CoQH₂/CoQ） 的比率，并通过反向电子传递 （RET） 从复合物 I 中的位点 I_Q 驱动过量的 mROS 产生。在体内使用多个互补的遗传和药理学模型，我们证明了 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，CoQH₂/CoQ 比率与疾病严重程度呈正相关。我们的数据确定了肥胖症中病理性 mROS 产生的高度选择性机制，可以靶向保护代谢稳态。