Journal Article

Mitochondrial ubiquinol oxidation is necessary for tumour growth

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

2020

Overview

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.

• Publisher: Nature Publishing Group UK,Nature Publishing Group
• Subject: 13/106 / 13/31 / 42 / 42/109 / 42/35 / 42/41 / 59/5 / 631/45/320 / 631/67/2327 / 64/60 / 82/29 / Alternative oxidase / Analysis / Animals / Anticancer properties / Brain tumors / Cancer / Cell Line, Tumor / Cell Proliferation / Ciona intestinalis - enzymology / Citric Acid Cycle / Cofactors / CRISPR / Cytochrome / Cytosol / Cytosol - metabolism / Dehydrogenases / Dihydroorotate Dehydrogenase / Ectopic expression / Electron Transport / Electron transport chain / Electron Transport Complex I - metabolism / Electron Transport Complex II - metabolism / Electron Transport Complex III - deficiency / Electron Transport Complex III - metabolism / Flavin-adenine dinucleotide / Growth / Humanities and Social Sciences / Humans / Influence / Levilactobacillus brevis - enzymology / Lung cancer / Male / Metabolites / Mice / Mitochondria / Mitochondria - enzymology / Mitochondria - metabolism / Mitochondrial biogenesis / Mitochondrial Proteins - genetics / Mitochondrial Proteins - metabolism / multidisciplinary / Multienzyme Complexes - genetics / Multienzyme Complexes - metabolism / NAD / NAD - metabolism / NADH / NADH oxidase / NADH, NADPH Oxidoreductases - genetics / NADH, NADPH Oxidoreductases - metabolism / NADH-ubiquinone oxidoreductase / Neoplasms - enzymology / Neoplasms - metabolism / Neoplasms - pathology / Nicotinamide adenine dinucleotide / Oxidase / Oxidation / Oxidation-reduction reaction / Oxidative Phosphorylation / Oxidoreductases - genetics / Oxidoreductases - metabolism / Oxidoreductases Acting on CH-CH Group Donors - metabolism / Phenotypes / Phosphorylation / Plant Proteins - genetics / Plant Proteins - metabolism / Regeneration / Science / Science (multidisciplinary) / Tricarboxylic acid cycle / Tumors / Ubiquinol / Ubiquinone / Ubiquinone - analogs & derivatives / Ubiquinone - metabolism / Ubiquinones