The mitochondrial electron transport chain (ETC) is necessary for tumour growth 1 – 6 and its inhibition has demonstrated anti-tumour efficacy in combination with targeted therapies 7 – 9 . Furthermore, human brain and lung tumours display robust glucose oxidation by mitochondria 10 , 11 . However, it is unclear why a functional ETC is necessary for tumour growth in vivo. ETC function is coupled to the generation of ATP—that is, oxidative phosphorylation and the production of metabolites by the tricarboxylic acid (TCA) cycle. Mitochondrial complexes I and II donate electrons to ubiquinone, resulting in the generation of ubiquinol and the regeneration of the NAD+ and FAD cofactors, and complex III oxidizes ubiquinol back to ubiquinone, which also serves as an electron acceptor for dihydroorotate dehydrogenase (DHODH)—an enzyme necessary for de novo pyrimidine synthesis. Here we show impaired tumour growth in cancer cells that lack mitochondrial complex III. This phenotype was rescued by ectopic expression of Ciona intestinalis alternative oxidase (AOX) 12 , which also oxidizes ubiquinol to ubiquinone. Loss of mitochondrial complex I, II or DHODH diminished the tumour growth of AOX-expressing cancer cells deficient in mitochondrial complex III, which highlights the necessity of ubiquinone as an electron acceptor for tumour growth. Cancer cells that lack mitochondrial complex III but can regenerate NAD+ by expression of the NADH oxidase from Lactobacillus brevis ( Lb NOX) 13 targeted to the mitochondria or cytosol were still unable to grow tumours. This suggests that regeneration of NAD+ is not sufficient to drive tumour growth in vivo. Collectively, our findings indicate that tumour growth requires the ETC to oxidize ubiquinol, which is essential to drive the oxidative TCA cycle and DHODH activity. Oxidation of ubiquinol by the mitochondrial electron transfer chain drives tumour growth by maintaining the function of the oxidative Krebs cycle and de novo pyrimidine synthesis.

中文翻译：

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线粒体泛醇氧化是肿瘤生长所必需的

线粒体电子传递链 (ETC) 对于肿瘤生长是必需的 1 – 6 ，其抑制作用已证明与靶向治疗相结合具有抗肿瘤功效 7 – 9 。此外，人脑和肺肿瘤显示出线粒体对葡萄糖的强烈氧化作用 10, 11 。然而，目前尚不清楚为什么功能性 ETC 对于体内肿瘤生长是必需的。ETC 功能与 ATP 的生成相关，即氧化磷酸化和三羧酸 (TCA) 循环产生代谢物。线粒体复合物 I 和 II 向泛醌提供电子，导致泛醇的生成以及 NAD+ 和 FAD 辅因子的再生，复合物 III 将泛醇氧化回泛醌，它还充当二氢乳清酸脱氢酶（DHODH）的电子受体，DHODH 是嘧啶从头合成所必需的酶。在这里，我们展示了缺乏线粒体复合物 III 的癌细胞中肿瘤生长受损。这种表型是通过海鞘替代氧化酶 (AOX) 12 的异位表达来挽救的，该酶也将泛醇氧化为泛醌。线粒体复合物 I、II 或 DHODH 的缺失会减少线粒体复合物 III 缺陷的表达 AOX 的癌细胞的肿瘤生长，这凸显了泛醌作为肿瘤生长的电子受体的必要性。缺乏线粒体复合物 III 但可以通过短乳杆菌 (Lb NOX) 13 靶向线粒体或细胞质的 NADH 氧化酶表达来再生 NAD+ 的癌细胞仍然无法生长肿瘤。这表明 NAD+ 的再生不足以驱动体内肿瘤生长。总的来说，我们的研究结果表明肿瘤生长需要 ETC 氧化泛醇，这对于驱动氧化 TCA 循环和 DHODH 活性至关重要。线粒体电子传递链对泛醇的氧化通过维持氧化克雷布斯循环和从头合成嘧啶的功能来驱动肿瘤生长。