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The Deubiquitinase Ubp3/Usp10 Constrains Glucose-Mediated Mitochondrial Repression Via Phosphate Budgeting

eLife(2024)SCI 1区

Inst Stem Cell Sci & Regenerat Med DBT InStem

Cited 1|Views5
Abstract
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.
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glycolysis,mitochondria,metabolic flux,inorganic phosphate,GAPDH,trehalose
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要点】:论文发现去泛素化酶Ubp3/Usp10通过调控磷酸盐预算限制高葡萄糖环境下线粒体的活性,揭示了细胞内磷酸盐平衡在调控线粒体抑制中的关键作用。

方法】:通过在Saccharomyces cerevisiae中进行筛选,识别出Ubp3/Usp10对线粒体抑制的重要性,并使用突变体和正交方法进行研究。

实验】:使用Δubp3细胞进行实验,发现高糖环境下糖酵解通量的持续消耗导致细胞内无机磷酸盐(Pi)受限,进而限制线粒体活化。通过比较Δubp3细胞与野生型细胞,发现代谢网络的重构和GAPDH的减少能够恢复Pi水平,导致线粒体Pi增加和活化。实验未明确提及具体数据集名称。