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.

3rd Faculty Hospital Charles University Prague Czech Republic

CNC Center for Neuroscience and Cell Biology University of Coimbra UC Biotech Biocant Park 3060 197 Cantanhede Portugal

College of Pharmacy Natural Product Research Institute Seoul National University Seoul 08826 Korea

Department of Biochemistry Radboud Institute for Molecular Life Sciences Radboud University Medical Centre 6525 Nijmegen the Netherlands

Department of Developmental and Stem Cell Biology Institut Pasteur 75015 Paris France; CNRS UMR 3738 Team Stability of Nuclear and Mitochondrial DNA 75015 Paris France

Eunice Kennedy Shriver Child Health and Human Development National Institutes of Health Bethesda MD USA

Faculty of Science Charles University 128 44 Prague Czech Republic

Institute for Glycomics Griffith University Southport 4222 QLD Australia

Institute of Biotechnology Czech Academy of Sciences 252 50 Vestec Prague West Czech Republic

Institute of Biotechnology Czech Academy of Sciences 252 50 Vestec Prague West Czech Republic; CNC Center for Neuroscience and Cell Biology University of Coimbra UC Biotech Biocant Park 3060 197 Cantanhede Portugal

Institute of Biotechnology Czech Academy of Sciences 252 50 Vestec Prague West Czech Republic; Faculty of Science Charles University 128 44 Prague Czech Republic

Institute of Biotechnology Czech Academy of Sciences 252 50 Vestec Prague West Czech Republic; School of Medical Science Griffith University Southport QLD 4222 Australia

Institute of Molecular Genetics Czech Academy of Sciences 142 20 Prague Czech Republic

Institute of Physiology Czech Academy of Sciences 142 20 Prague Czech Republic

Malaghan Institute of Medical Research Wellington 6242 New Zealand

School of Medical Science Griffith University Southport QLD 4222 Australia

Victor Chang Cardiac Research Institute Darlinghurst NSW 2010 Australia; St Vincent's Clinical School UNSW Medicine University of New South Wales Sydney NSW 2052 Australia

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