美国西北大学芬伯格医学院Navdeep S. Chandel研究团队近日取得一项新成果。经过不懈努力，他们发现线粒体泛醌氧化是肿瘤生长所必需的。这一研究成果于2020年7月8日在线发表在《自然》上。

研究人员发现缺乏线粒体复合物III的癌细胞生长受损。该表型可通过异位表达玻璃海鞘替代氧化酶（AOX）挽救，该酶将泛醇氧化为泛醌。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但通过表达短乳杆菌（LbNOX）NADH氧化酶来再生NAD ⁺的癌细胞仍然无法生长，该酶作用于线粒体或细胞质。这表明NAD ⁺的再生不足以在体内促进肿瘤生长。

总的来说，该研究表明肿瘤的生长需要线粒体电子传输链（ETC）氧化泛醇，这对于诱导氧化三羧酸（TCA）循环和DHODH活性至关重要。

据悉，ETC是肿瘤生长所必需的，已证明抑制其作用与靶向疗法相结合的方法具有抗肿瘤功效。此外，人脑和肺部肿瘤表现出线粒体强烈的葡萄糖氧化功能。然而，尚不清楚为什么功能性ETC对于体内肿瘤生长是必需的。ETC的功能是产生ATP，这是通过TCA循环的氧化磷酸化与代谢产物产生完成的。线粒体复合物I和II将电子提供给泛醌，导致泛醇的生成以及NAD ⁺和FAD辅因子的再生，而复合物III将泛醇氧化为泛醌，泛醌还作为DHODH的电子受体，是从头合成嘧啶所需的酶。

附：英文原文

Title: Mitochondrial ubiquinol oxidation is necessary for tumour growth

Author: Inmaculada Martnez-Reyes, Luzivette Robles Cardona, Hyewon Kong, Karthik Vasan, Gregory S. McElroy, Marie Werner, Hermon Kihshen, Colleen R. Reczek, Samuel E. Weinberg, Peng Gao, Elizabeth M. Steinert, Raul Piseaux, G. R. Scott Budinger, Navdeep S. Chandel

Issue&Volume: 2020-07-08

Abstract: The mitochondrial electron transport chain (ETC) is necessary for tumour growth1,2,3,4,5,6 and its inhibition has demonstrated anti-tumour efficacy in combination with targeted therapies7,8,9. Furthermore, human brain and lung tumours display robust glucose oxidation by mitochondria10,11. 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 (LbNOX)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.

DOI: 10.1038/s41586-020-2475-6

Source: https://www.nature.com/articles/s41586-020-2475-6