期刊
CELL METABOLISM
卷 29, 期 2, 页码 399-+出版社
CELL PRESS
DOI: 10.1016/j.cmet.2018.10.014
关键词
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资金
- Australian Research Council Discovery grant
- Czech Science Foundation [15-02203S, 16-12719S, 17-07635S, 17-0192J, 17-20904S, 1622823S, 16-12816S, 18-24753Y, 18-11275S, 18-02550S]
- Czech Health Research Council [16-31604A, 17-30138A]
- Czech Academy of Sciences [RVO: 86652036]
- Ministry of Education, Youth and Sports of the Czech Republic [LQ1604]
- ERDF [CZ.1.05/1.100, CZ.2.16/3.1.00/21531]
- National Health and Medical Research Council [1059775, 1083450]
- FEDER funds through the Operational Program Competitiveness Factors - COMPETE
- FCT - Foundation for Science and Technology [PTDC/DTP-FTO/2433/2014, POCI-01-0145-FEDER-016659, POCI-01-0145-FEDER-007440, POCI-01-0145-FEDER-016390]
- National Health & Medical Research Council Senior Principal Research Fellowship [1111632]
- Health Research Council of New Zealand
- Cancer Society of New Zealand
- Malaghan Institute
- Intramural Research Program of the NIH, NICHD
- Technology Agency of the Czech Republic [TE01020118]
- framework of international cooperation program [NRF-2016K2A9A1A06921853]
- National Research Foundation of Korea (NRF) grant - Korea government (MSIT) [NRF-2018R1A3B1052328]
- DARRI [14/152]
- FCT PhD scholarship [SFRH/BD/103399/2014]
- Grant Agency of Charles University [GA UK 362015, GA UK 1100217, GA UK 1552218, GA UK 1560218]
- Czech-BioImaging large RI projects - MEYS CR [LM2015062, CZ.02.1.01/0.0/0.0/16_013/0001775]
- MEYS CR [LM2015062]
- EUNICE KENNEDY SHRIVER NATIONAL INSTITUTE OF CHILD HEALTH & HUMAN DEVELOPMENT [ZIAHD008735] Funding Source: NIH RePORTER
- National Health and Medical Research Council of Australia [1083450, 1059775] Funding Source: NHMRC
- Fundação para a Ciência e a Tecnologia [SFRH/BD/103399/2014] Funding Source: FCT
Cancer cells without mitochondrial DNA ( mtDNA) do not form tumors unless they reconstitute oxidative phosphorylation (OXPHOS) by mitochondria acquired from host stroma. To understand why functional respiration is crucial for tumorigenesis, we used time-resolved analysis of tumor formation by mtDNA-depleted cells and genetic manipulations of OXPHOS. We show that pyrimidine biosynthesis dependent on respiration-linked dihydroorotate dehydrogenase (DHODH) is required to overcome cell-cycle arrest, while mitochondrial ATP generation is dispensable for tumorigenesis. Latent DHODH in mtDNA-deficient cells is fully activated with restoration of complex III/IV activity and coenzyme Q redox-cycling after mitochondrial transfer, or by introduction of an alternative oxidase. Further, deletion of DHODH interferes with tumor formation in cells with fully functional OXPHOS, while disruption of mitochondrial ATP synthase has little effect. Our results show that DHODH-driven pyrimidine biosynthesis is an essential pathway linking respiration to tumorigenesis, pointing to inhibitors of DHODH as potential anti-cancer agents.
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