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

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 screen, we identified the conserved deubiquitinase Ubp3 (Usp10), as necessary for mitochondrial...

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Bibliographic Details
Published in:eLife 2024-09, Vol.12
Main Authors: Vengayil, Vineeth, Niphadkar, Shreyas, Adhikary, Swagata, Varahan, Sriram, Laxman, Sunil
Format: Article
Language:English
Subjects:
Biochemistry and Chemical Biology
Budget
Cancer Biology
Cell activation
Derepression
Dextrose
Endopeptidases
Enzymes
Ethanol
GAPDH
Glucose
Glucose - metabolism
Glycolysis
Graph representations
inorganic phosphate
Libraries
metabolic flux
Metabolic networks
Metabolism
Metabolites
Mitochondria
Mitochondria - metabolism
Phosphates
Phosphates - metabolism
Phosphorylation
Physiological aspects
Proteins
Respiration
Saccharomyces cerevisiae - genetics
Saccharomyces cerevisiae - metabolism
Saccharomyces cerevisiae Proteins - genetics
Saccharomyces cerevisiae Proteins - metabolism
Trehalose
Trehalose - metabolism
Ubiquitin Thiolesterase - genetics
Ubiquitin Thiolesterase - metabolism
Yeast
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Summary: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 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 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 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.
ISSN:2050-084X
2050-084X
DOI:10.7554/eLife.90293