Mitochondrial ubiquinol oxidation is necessary for tumour growth.

Abstract

The mitochondrial electron transport chain (ETC) is necessary for tumor growth1–6 and its inhibition has demonstrated efficacy in combination with immuno-, antiangiogenic, or oncogene targeted-therapies7–9. Furthermore, brain and lung human tumors display robust glucose oxidation by mitochondria10,11. However, it is not fully understood why a functional ETC is necessary for tumor growth in vivo. ETC function is coupled to the generation of ATP, i.e. oxidative phosphorylation (OXPHOS) and the production of TCA cycle metabolites. Mitochondrial complex I and II donate electrons to ubiquinone resulting in the generation of ubiquinol. This allows regeneration of NAD+ and FAD, necessary cofactors for oxidative TCA cycle flux. Mitochondrial complex III oxidizes ubiquinol back to ubiquinone to allow complexes I and II to function. The ubiquinone generated by complex III is also used as an electron acceptor by the only mitochondrial enzyme essential for de novo pyrimidine synthesis, dihydroorotate dehydrogenase (DHODH). We observed impaired tumor growth in cancer cells lacking mitochondrial complex III. This phenotype was rescued by ectopic expression of Ciona intestinalis alternative oxidase (AOX) 12 that also oxidizes ubiquinol to ubiquinone. Loss of mitochondrial complex I, II, or DHODH diminished the tumor growth of AOX expressing cancer cells deficient in mitochondrial complex III, highlighting the necessity of ubiquinone as an electron acceptor for tumor 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 still failed to grow tumors. This suggests that NAD+ regeneration is not sufficient to drive tumor growth in vivo. Collectively, our findings indicate that tumor growth requires the ETC to oxidize ubiquinol which is essential to drive oxidative TCA cycle and DHODH activity.