The oxidative phosphorylation system¹ in mammalian mitochondria plays a key role in transducing energy from ingested nutrients². Mitochondrial metabolism is dynamic and can be reprogrammed to support both catabolic and anabolic reactions, depending on physiological demands or disease states. Rewiring of mitochondrial metabolism is intricately linked to metabolic diseases and promotes tumour growth^3,4,5. Here, we demonstrate that oral treatment with an inhibitor of mitochondrial transcription (IMT)⁶ shifts whole-animal metabolism towards fatty acid oxidation, which, in turn, leads to rapid normalization of body weight, reversal of hepatosteatosis and restoration of normal glucose tolerance in male mice on a high-fat diet. Paradoxically, the IMT treatment causes a severe reduction of oxidative phosphorylation capacity concomitant with marked upregulation of fatty acid oxidation in the liver, as determined by proteomics and metabolomics analyses. The IMT treatment leads to a marked reduction of complex I, the main dehydrogenase feeding electrons into the ubiquinone (Q) pool, whereas the levels of electron transfer flavoprotein dehydrogenase and other dehydrogenases connected to the Q pool are increased. This rewiring of metabolism caused by reduced mtDNA expression in the liver provides a principle for drug treatment of obesity and obesity-related pathology.

哺乳动物线粒体中的氧化磷酸化系统¹在从摄入的营养物质²中转换能量方面发挥着关键作用。线粒体代谢是动态的，可以根据生理需求或疾病状态进行重新编程以支持分解代谢和合成代谢反应。线粒体代谢的重新布线与代谢疾病密切相关，并促进肿瘤生长^3,4,5 。在此，我们证明口服线粒体转录抑制剂 (IMT) ⁶的治疗可将整个动物的代谢转向脂肪酸氧化，从而导致体重快速正常化、逆转肝脂肪变性并恢复正常的葡萄糖耐量。高脂肪饮食的雄性小鼠。矛盾的是，蛋白质组学和代谢组学分析表明，IMT 治疗会导致氧化磷酸化能力严重降低，同时肝脏中脂肪酸氧化显着上调。 IMT 处理导致复合物 I 显着减少，复合物 I 是向泛醌 (Q) 池提供电子的主要脱氢酶，而电子转移黄素蛋白脱氢酶和与 Q 池连接的其他脱氢酶的水平增加。这种由肝脏中 mtDNA 表达减少引起的代谢重新布线为肥胖和肥胖相关病理的药物治疗提供了原则。