2025
Cancer Research

Mitochondrial Transfer Rescues Respiration to Support De Novo Pyrimidine Biosynthesis and Tumor Progression

Authors:

Maria Dubisova; Klara Bohacova; Zuzana Nahacka; Daniel Kraus; Jaromir Novak; Sarka Dvorakova; Petra Brisudova; Natalie Danesova; Saba Selvi; Mariia Hrysiuk; Berwini B. Endaya; Panagiotis Botsios; Dan-Diem Thi. Le; Monika Novotna; Sona Vodenkova; Jaroslav Truksa; Karel Chalupsky; Krystof Klima; Jan Prochazka; Radislav Sedlacek; Francesco Mengarelli; Patrick Orlando; Luca Tiano; Stepana Boukalova; Michael V. Berridge; Renata Zobalova; Jiri Neuzil

Keywords:

Cancer; mtDNA; mitochondrial DNA; horizontal mitochondrial transfer; DHODH; de novo pyrimidine synthesis; tumor; mitochondrial respiratory complex III; mitochondrial respiratory complexes IV; mesenchymal stromal cell; mitochondrial donor; pyrimidine synthesis; tumor microenvironment

Abstract:

Cancer cells with severe defects in mitochondrial DNA (mtDNA) can import mitochondria via horizontal mitochondrial transfer (HMT) to restore respiration. Mitochondrial respiration is necessary for the activity of dihydroorotate dehydrogenase (DHODH), an enzyme of the inner mitochondrial membrane that catalyzes the fourth step of de novo pyrimidine synthesis. Here, we investigated the role of de novo synthesis of pyrimidines in driving tumor growth in mtDNA-deficient (ρ0) cells. While ρ0 cells grafted in mice readily acquired mtDNA, this process was delayed in cells transfected with alternative oxidase (AOX), which combines the functions of mitochondrial respiratory complexes III and IV. The ρ0 AOX cells were glycolytic but maintained normal DHODH activity and pyrimidine production. Deletion of DHODH in a panel of tumor cells completely blocked or delayed tumor growth. The grafted ρ0 cells rapidly recruited tumor-promoting/stabilizing cells of the innate immune system, including pro-tumor M2 macrophages, neutrophils, eosinophils, and mesenchymal stromal cells (MSCs). The ρ0 cells recruited MSCs early after grafting, which were potential mitochondrial donors. Grafting MSCs together with ρ0 cancer cells into mice resulted in mitochondrial transfer from MSCs to cancer cells. Overall, these findings indicate that cancer cells with compromised mitochondrial function readily acquire mtDNA from other cells in the tumor microenvironment to restore DHODH-dependent respiration and de novo pyrimidine synthesis. The inhibition of tumor growth induced by blocking DHODH supports targeting pyrimidine synthesis as a potential widely applicable therapeutic approach.