ArticleNature metabolism2026
Ectopic expression of cytosolic DHODH uncouples de novo pyrimidine biosynthesis from mitochondrial electron transport.
Article in Nature metabolism, 2026. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 5 papers.
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Who cites it
5 citing papers in PubMed.
- Exploring the Role of the LCN2-DHODH Interaction in Mitochondrial Ferroptosis During Sepsis-Induced Myocardial Injury and LPS-Induced HL-1 Cardiomyocyte Injury.International journal of molecular sciences · 2026Article
- DHODH turns cytosolic, yet cells keep growing.Nature metabolism · 2026Article
- Ferroptosis as an Emerging Therapeutic Target in Allergic Diseases.Drug design, development and therapy · 2026Review
- Cytochrome c oxidase dependent respiration is essential for T cell activation, proliferation and memory formation.Nature communications · 2025Article
- Xenotopic synthetic biology: Prospective tools for delaying aging and age-related diseases.Science advances · 2025Review
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Authors and funding
11 authors.
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Abstract
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 ρ
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