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Many cells growing in high glucose repress mitochondrial respiration, as observed in the Crabtree and Warburg effects. A parsimonious biochemical explanation for this phenomenon is missing. Using a Saccharomyces cerevisiae screen, we identified the conserved deubiquitinase Ubp3 (Usp10), as necessary for proper mitochondrial repression. Ubp3 mutants have increased mitochondrial activity despite abundant glucose, with downregulated glycolytic enzymes, rewired glucose metabolism, and increased trehalose. Utilizing ∆ubp3 cells, along with orthogonal approaches, we find that the Crabtree effect is driven mechanistically by controling mitochondrial access of inorganic phosphate (Pi), as determined by glycolytic flux. High glycolytic flux consumes free Pi, limiting available Pi for entry into the mitochondria. Cytosolic Pi-dependent mitochondrial Pi entry is necessary and sufficient to derepress mitochondria, driving synchronous requirements to sustain mitochondrial activity. Restricting Pi entry to the mitochondria prevents mitochondrial derepression. Collectively, we propose a biochemical basis of mitochondrial repression in high-glucose based on intracellular Pi budgeting.

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