
The author argues that intracellular Pi budgeting between glycolysis and mitochondria is a key constraint for mitochondrial repression, controlled by Ubp3 through regulating glycolytic enzymes. This results in increased Pi availability to mitochondria, influencing mitochondrial activity.


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Many cells in high glucose repress mitochondrial respiration, as observed in the Crabtree and Warburg effects. Our understanding of biochemical constraints for mitochondrial activation is limited. Using a Saccharomyces cerevisiae screen, we identified the conserved deubiquitinase Ubp3 (Usp10), as necessary for mitochondrial repression. Ubp3 mutants have increased mitochondrial activity despite abundant glucose, along with decreased glycolytic enzymes, and a rewired glucose metabolic network with increased trehalose production. Utilizing Δubp3 cells, along with orthogonal approaches, we establish that the high glycolytic flux in glucose continuously consumes free Pi. This restricts mitochondrial access to inorganic phosphate (Pi), and prevents mitochondrial activation. Contrastingly, rewired glucose metabolism with enhanced trehalose production and reduced GAPDH (as in Δubp3 cells) restores Pi. This collectively results in increased mitochondrial Pi and derepression, while restricting mitochondrial Pi transport prevents activation. We therefore suggest that glycolytic-flux dependent intracellular Pi budgeting is a key constraint for mitochondrial repression.

### Competing Interest Statement

The authors have declared no competing interest.

The deubiquitinase Ubp3/Usp10 constrains glucose-mediated mitochondrial repression via phosphate budgeting

understanding-the-role-of-pi-budgeting-in-glucose-mediated-mitochondrial-repression


Understanding the Role of Pi Budgeting in Glucose-Mediated Mitochondrial Repression
