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.

• Klíčová slova
• OXPHOS, cancer, coenzyme Q, dihydroorotate dehydrogenase, mitochondria, pyrimidine biosynthesis, respiration,
• MeSH
• buněčné dýchání MeSH
• dihydroorotátdehydrogenasa MeSH
• lidé MeSH
• mitochondriální DNA metabolismus   MeSH
• mitochondrie metabolismus   MeSH
• myši inbrední BALB C MeSH
• myši inbrední C57BL MeSH
• myši MeSH
• nádorové buněčné linie MeSH
• nádory metabolismus   MeSH
• oxidativní fosforylace MeSH
• oxidoreduktasy působící na CH-CH vazby fyziologie   MeSH
• pyrimidiny metabolismus   MeSH
• ubichinon metabolismus   MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• myši MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Research Support, N.I.H., Intramural MeSH
• Názvy látek
• dihydroorotátdehydrogenasa MeSH
• mitochondriální DNA MeSH
• oxidoreduktasy působící na CH-CH vazby MeSH
• pyrimidine MeSH Prohlížeč
• pyrimidiny MeSH
• ubichinon MeSH

Cell growth and survival depend on a delicate balance between energy production and synthesis of metabolites. Here, we provide evidence that an alternative mitochondrial complex II (CII) assembly, designated as CIIlow, serves as a checkpoint for metabolite biosynthesis under bioenergetic stress, with cells suppressing their energy utilization by modulating DNA synthesis and cell cycle progression. Depletion of CIIlow leads to an imbalance in energy utilization and metabolite synthesis, as evidenced by recovery of the de novo pyrimidine pathway and unlocking cell cycle arrest from the S-phase. In vitro experiments are further corroborated by analysis of paraganglioma tissues from patients with sporadic, SDHA and SDHB mutations. These findings suggest that CIIlow is a core complex inside mitochondria that provides homeostatic control of cellular metabolism depending on the availability of energy.

• MeSH
• biosyntetické dráhy fyziologie   MeSH
• energetický metabolismus fyziologie   MeSH
• fyziologický stres * MeSH
• genový knockout MeSH
• HEK293 buňky MeSH
• kontrolní body fáze S buněčného cyklu fyziologie   MeSH
• lidé MeSH
• malá interferující RNA metabolismus   MeSH
• mitochondrie metabolismus   MeSH
• mutace MeSH
• myši inbrední BALB C MeSH
• myši nahé MeSH
• myši MeSH
• nádorové buněčné linie MeSH
• paragangliom genetika   patologie   MeSH
• respirační komplex II genetika   metabolismus   MeSH
• sukcinátdehydrogenasa genetika   metabolismus   MeSH
• xenogenní modely - testy antitumorózní aktivity MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• myši MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• malá interferující RNA MeSH
• respirační komplex II MeSH
• respiratory complex II MeSH Prohlížeč
• SDHA protein, human MeSH Prohlížeč
• SDHB protein, human MeSH Prohlížeč
• sukcinátdehydrogenasa MeSH