Transcriptomics

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The Metabolostasis System Regulates the Aggregation and Toxicity of Essential Metabolites


ABSTRACT: Although metabolites are essential across all branches of life, it has been recently reported that they can form cytotoxic aggregates that resemble those formed by proteins in misfolding diseases. The phenomenon of metabolite aggregation suggests the existence of a metabolite homeostasis (metabolostasis) system capable of maintaining metabolites within a concentration range optimal for cellular function. To investigate this system, using Saccharomyces cerevisiae as a model organism, we identified the critical upper limits of metabolite consumption, beyond which metabolostasis is disrupted, leading to toxicity and growth inhibition. By enforcing a metabolite intake near the upper limits, we monitored the changes at the metabolome, transcriptome, and proteome levels, enabling us to map the metabolostasis system. Among the most affected pathways, we identified oxidative phosphorylation and intracellular membrane trafficking, particularly within the vacuole, which emerges as a containment and detoxification hub for potentially toxic metabolites. Near the upper limits of metabolite consumption, we observed the formation of amyloid-like metabolite aggregates, suggesting that the cytotoxicity is, at least in part, related to the conformational state of the metabolites and, in turn, the physicochemical properties that determine their solubility. Our findings characterize metabolostasis as the cellular system that maintains metabolites within their safe concentration limits and prevents their aberrant accumulation into cytotoxic aggregates.

ORGANISM(S): Saccharomyces cerevisiae

PROVIDER: GSE285470 | GEO | 2025/11/05

REPOSITORIES: GEO

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