Bajzikova 2019 Cell Metab

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Bajzikova M, Kovarova J, Coelho AR, Boukalova S, Oh S, Rohlenova K, Svec D, Hubackova S, Endaya B, Judasova K, Bezawork-Geleta A, Kluckova K, Chatre L, Zobalova R, Novakova A, Vanova K, Ezrova Z, Maghzal GJ, Magalhaes Novais S, Olsinova M, Krobova L, An YJ, Davidova E, Nahacka Z, Sobol M, Cunha-Oliveira T, Sandoval-AcuΓ±a C, Strnad H, Zhang T, Huynh T, Serafim TL, Hozak P, Sardao VA, Koopman Werner JH, Ricchetti M, Oliveira PJ, Kolar F, Kubista M, Truksa J, Dvorakova-Hortova K, Pacak K, Gurlich R, Stocker R, Zhou Y, Berridge MV, Park S, Dong L, Rohlena J, Neuzil J (2019) Reactivation of dihydroorotate dehydrogenase-driven pyrimidine biosynthesis restores tumor growth of respiration-deficient cancer cells. Cell Metab 29:399-416. 10.1016/j.cmet.2018.10.014

Β» PMID: 30449682 Open Access

Bajzikova Martina, Kovarova Jaromira, Coelho Ana R, Boukalova Stepana, Oh Sehyun, Rohlenova Katerina, Svec David, Hubackova Sona, Endaya Berwini, Judasova Kristyna, Bezawork-Geleta Ayenachew, Kluckova Katarina, Chatre Laurent, Zobalova Renata, Novakova Anna, Vanova Katerina, Ezrova Zuzana, Maghzal Ghassan J, Magalhaes Novais Silvia, Olsinova Marie, Krobova Linda, An Yong Jin, Davidova Eliska, Nahacka Zuzana, Sobol Margarita, Cunha-Oliveira Teresa, Sandoval-Acuna Cristian, Strnad Hynek, Zhang Tongchuan, Huynh Thanh, Serafim Teresa L, Hozak Pavel, Sardao Vilma A, Koopman Werner JH, Ricchetti Miria, Oliveira Paulo J, Kolar Frantisek, Kubista Mikael, Truksa Jaroslav, Dvorakova-Hortova Katerina, Pacak Karel, Gurlich Robert, Stocker Roland, Zhou Yaoqi, Berridge Michael V, Park Sunghyouk, Dong Lanfeng, Rohlena Jakub, Neuzil Jiri (2019) Cell Metab

Abstract: 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. β€’ Keywords: OXPHOS, Cancer, Coenzyme Q, Dihydroorotate dehydrogenase, Mitochondria, Pyrimidine biosynthesis, Respiration β€’ Bioblast editor: Plangger M β€’ O2k-Network Lab: CZ Prague Neuzil J, AU Queensland Neuzil J, NL Nijmegen Koopman WJ, AU Sydney Stocker R, AU Queensland Peart J

Labels: MiParea: Respiration, Genetic knockout;overexpression  Pathology: Cancer 

Organism: Mouse  Tissue;cell: Endothelial;epithelial;mesothelial cell, Genital, Other cell lines  Preparation: Permeabilized cells, Homogenate  Enzyme: Complex I, Complex II;succinate dehydrogenase, Complex III, Complex V;ATP synthase 

Coupling state: OXPHOS, ET  Pathway: N, S, ROX  HRR: Oxygraph-2k 

2018-11, PBI-Shredder 

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