Mitochondrial ubiquinol oxidation is necessary for tumor growth
| Autor: | Navdeep S. Chandel, Marie Werner, Colleen R. Reczek, Inmaculada Martínez-Reyes, G. R. Scott Budinger, Hyewon Kong, Elizabeth M. Steinert, Gregory S. McElroy, Samuel E. Weinberg, Peng Gao, Karthik Vasan, Raul Piseaux, Hermon Kihshen, Luzivette Robles Cardona |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2020 |
| Předmět: |
0301 basic medicine
Male Alternative oxidase Ubiquinol Oxidoreductases Acting on CH-CH Group Donors Ubiquinone Citric Acid Cycle Levilactobacillus brevis Dihydroorotate Dehydrogenase Oxidative phosphorylation Mitochondrion Article Oxidative Phosphorylation Electron Transport Mitochondrial Proteins 03 medical and health sciences chemistry.chemical_compound Electron Transport Complex III Mice 0302 clinical medicine Cytosol Multienzyme Complexes Cell Line Tumor Neoplasms Animals Humans NADH NADPH Oxidoreductases Cell Proliferation Plant Proteins Multidisciplinary Electron Transport Complex I Chemistry Electron Transport Complex II NAD Ciona intestinalis Mitochondria Citric acid cycle 030104 developmental biology Biochemistry 030220 oncology & carcinogenesis Coenzyme Q – cytochrome c reductase Dihydroorotate dehydrogenase NAD+ kinase Oxidoreductases |
| Zdroj: | Nature |
| ISSN: | 1476-4687 0028-0836 |
| Popis: | The mitochondrial electron transport chain (ETC) is necessary for tumour growth1–6 and its inhibition has demonstrated anti-tumour efficacy in combination with targeted therapies7–9. 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. 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. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|
Full text from SpringerLink