Partial inhibition of mitochondrial-linked pyrimidine synthesis increases tumorigenic potential and lysosome accumulation

The correlation between mitochondrial function and oncogenesis is complex and is not fully understood. Here we determine the importance of mitochondrial-linked pyrimidine synthesis for the aggressiveness of cancer cells. The enzyme dihydroorotate dehydrogenase (DHODH) links oxidative phosphorylation...

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Bibliographic Details
Published in:Mitochondrion 2022-05, Vol.64, p.73-81
Main Authors: Desler, Claus, Durhuus, Jon Ambæk, Hansen, Thomas Lau-Lindestrand, Anugula, Sharath, Zelander, Nadia Thaulov, Bøggild, Sisse, Rasmussen, Lene Juel
Format: Article
Language:English
Subjects:
Carcinogenesis
Dihydroorotate Dehydrogenase
DNA repair
Humans
Lysosome increase
Lysosomes
Mitochondria
Mitochondrial-linked pyrimidine synthesis
Oxidoreductases Acting on CH-CH Group Donors - genetics
Pyrimidines
Tumorigenesis
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Summary:The correlation between mitochondrial function and oncogenesis is complex and is not fully understood. Here we determine the importance of mitochondrial-linked pyrimidine synthesis for the aggressiveness of cancer cells. The enzyme dihydroorotate dehydrogenase (DHODH) links oxidative phosphorylation to de novo synthesis of pyrimidines. We demonstrate that an inhibition of DHODH results in a respiration-independent significant increase of anchorage-independent growth but does not affect DNA repair ability. Instead, we show an autophagy-independent increase of lysosomes. The results of this study suggest that inhibition of mitochondrial-linked pyrimidine synthesis in cancer cells results in a more aggressive tumor phenotype.
ISSN:1567-7249
1872-8278
DOI:10.1016/j.mito.2022.03.005