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

The paper shows that expressing a yeast cytosolic DHODH (Sc URA) in mammalian cells decouples de novo pyrimidine biosynthesis from the mitochondrial electron-transport chain by using fumarate instead of ubiquinone as an electron acceptor, enabling respiration-independent nucleotide synthesis. As a result, cells with Sc URA resist inhibition of respiratory complex III or mitochondrial ribosomes and can proliferate without exogenous uridine even when mitochondrial function is compromised. This uncoupling reveals that pyrimidine synthesis drives key phenotypes of mitochondrial dysfunction and offers a genetic strategy to bypass respiration-linked biosynthetic blocks.

Source : https://www.nature.com/articles/s42255-026-01454-7