Unravelling “Metabolostasis”: a genome-wide approach for elucidating homeostasis of metabolite aggregation in physiology and pathology

Metabolism describes the complex network of reactions that enable organisms to generate the energy and the biological building blocks – metabolites – that are required to sustain life. The paramount role metabolites play across the branches of life, as well as their part in various disorders, has been investigated for decades. Yet, only recently it has been revealed that these life-essential building blocks can form cytotoxic aggregates, which resemble those found in proteinopathies such as Alzheimer’s disease and Parkinson`s disease. This discovery raises elementary questions regarding the metabolite homeostasis – “metabolostasis” – mechanisms that maintain metabolites in a soluble non-aggregative state. Such quality-control mechanisms must allow the sufficient supply of metabolites on one hand, while strictly maintaining them at sub-aggregative concentrations in the crowded cellular environment and evading the toxic effects of preformed metabolite assemblies. When the fine balance between metabolite solubility and aggregation is compromised, metabolites self-assemble into toxic species that lead to various pathological phenotypes. Yet, the mechanisms that maintain metabolites at a non-toxic state, and the mechanisms that mediate the toxicity of metabolite aggregates in pathologies, remain unknown.

Here we apply advanced high-throughput genetic tools in yeast for genome-wide analysis, aimed at elucidating the metabolostasis network of ubiquitous amino acids and nucleobases. With this research, we aim to establish the novel concept of metabolostasis and unravel the fundamental cellular mechanisms that maintain metabolites in their non-aggregative state, as well as elucidate the consequences of compromised metabolostasis in pathological conditions.