The mitochondrial electron transport chain (ETC) is necessary for tumour growth and its inhibition has demonstrated anti-tumour efcacy in combination with targeted therapies . Furthermore, human brain and lung tumours display robust glucose oxidation by mitochondria. 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 (LbNOX)13 targeted to the mitochondria or cytosol were still unable to grow tumours. This suggests that regeneration of NAD+ is not suffcient to drive tumour growth in vivo. Collectively, our fndings indicate that tumour growth requires the ETC to oxidize ubiquinol, which is essential to drive the oxidative TCA cycle and DHODH activity. 线粒体电子传递链对于肿瘤生长是必需的。并且它的抑制作用已经在联合靶向治疗中证实了抗肿瘤的疗效。其次，人类大脑和肺部肿瘤，线粒体会氧化大量的葡萄糖。然而，为何一个功能性的电子传递链在体内对于肿瘤的生长是必需的，这仍然不清楚。ETC的功能是与ATP的产生相耦合---也就是氧化磷酸化，以及产生三羧酸循环的代谢物。线粒体复合体I和II将电子传递给泛醌,导致了泛醇的产生以及NAD+和FAD辅酶因子的再生，并且复合体III氧化泛醇，使之回至泛醌，它也是二氢乳清酸脱氢酶的电子受体（DHODH）-----这是嘧啶合成时所必需的酶。在这里，我们证实了癌细胞中缺乏线粒体复合体III会抑制肿瘤生长。而这种表型可以被异位表达玻璃海鞘替代氧化酶（AOX）挽救，AOX也可以将泛醇氧化为泛醌。线粒体复合物I、II或二氢乳清酸脱氢酶（DHODH）的缺失使得线粒体复合物III缺乏且表达AOX的癌细胞的生长受损，这突出了泛醌作为肿瘤生长电子受体的必要性。缺乏线粒体复合物III但是可以通过来自短乳杆菌（LbNOX）的靶向于线粒体细胞质的NADH氧化酶再生NAD+的癌细胞仍然无法生长。这意味着NAD+的再生并不是使肿瘤细胞生长所必要的。因此，我们的结果表明，肿瘤生长需要ETC来氧化泛醇，这对于驱动氧化三羧酸循环和DHODH活性至关重要。 |
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