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<p>Dihydroorotate dehydrogenase is a rate-limiting enzyme of de novo pyrimidine synthesis. In most eukaryotes, this enzyme is bound to the inner mitochondrial membrane, where it couples orotate synthesis to ubiquinone reduction. As ubiquinone must be regenerated by respiratory complex III, pyrimidine biosynthesis and cellular respiration are tightly coupled. Consequently, inhibition of respiration suppresses DNA synthesis and cell proliferation. Here we show that expression of the <i>Saccharomyces cerevisiae</i> URA1 gene (<i>Sc</i>URA) in mammalian cells uncouples pyrimidine biosynthesis from mitochondrial electron transport. <i>Sc</i>URA forms a homodimer in the cytosol that uses fumarate as an electron acceptor instead of ubiquinone, enabling respiration-independent pyrimidine biosynthesis. Cells expressing <i>Sc</i>URA are resistant to drugs that inhibit complex III and the mitochondrial ribosome. Additionally, <i>Sc</i>URA enables growth of mitochondrial-DNA-lacking ρ<sup>0</sup> cells in uridine-deficient medium and ameliorates the phenotype of cellular models of mitochondrial diseases. Overall, this genetic tool uncovers the contribution of pyrimidine biosynthesis to the phenotypes arising from electron transport chain defects.</p>

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Ectopic expression of cytosolic DHODH uncouples de novo pyrimidine biosynthesis from mitochondrial electron transport

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年2月17日

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  • Andrea Curtabbi,
  • Sara Natalia Jaroszewicz,
  • Rocío Sanz-Cortés,
  • Rebeca Acín-Pérez,
  • Dimitrios Prymidis,
  • Maksym Cherevatenko,
  • Raquel Martínez-de-Mena,
  • María Jesús Esteban-Amo,
  • Miguel A. de la Fuente,
  • Christian Frezza,
  • José Antonio Enríquez

摘要

Dihydroorotate dehydrogenase is a rate-limiting enzyme of de novo pyrimidine synthesis. In most eukaryotes, this enzyme is bound to the inner mitochondrial membrane, where it couples orotate synthesis to ubiquinone reduction. As ubiquinone must be regenerated by respiratory complex III, pyrimidine biosynthesis and cellular respiration are tightly coupled. Consequently, inhibition of respiration suppresses DNA synthesis and cell proliferation. Here we show that expression of the Saccharomyces cerevisiae URA1 gene (ScURA) in mammalian cells uncouples pyrimidine biosynthesis from mitochondrial electron transport. ScURA forms a homodimer in the cytosol that uses fumarate as an electron acceptor instead of ubiquinone, enabling respiration-independent pyrimidine biosynthesis. Cells expressing ScURA are resistant to drugs that inhibit complex III and the mitochondrial ribosome. Additionally, ScURA enables growth of mitochondrial-DNA-lacking ρ0 cells in uridine-deficient medium and ameliorates the phenotype of cellular models of mitochondrial diseases. Overall, this genetic tool uncovers the contribution of pyrimidine biosynthesis to the phenotypes arising from electron transport chain defects.