Unraveling Metabolostasis: how did mechanisms preventing metabolite aggregation emerge throughout evolution?

Metabolism describes the complex network of reactions that enable organisms to generate the energy and molecules, metabolites, they need to thrive. 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, similar to those found in neurodegenerative disorders such as Alzheimer’s disease and Parkinson's disease. This discovery raises elementary questions regarding 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 monitoring their levels and avoid aggregation on the other. These mechanisms, we believe, have co-evolved with the metabolites themselves, and originated very early in the evolutionary timeline. Here, we will tackle these questions by applying advanced high-throughput genetic tools, combined with an innovative robotic automated visualization platform to provide novel insights into this central mechanism. Implemented in both eukaryote and prokaryote models, this integrated system will provide a multi-systemic evolutionary exploration into this uncharted territory and will allow identifying, for the first time, the cellular mechanisms of metabolostasis. As metabolites have been present at primordial earth, we will also study the ability of these molecules to form stable catalytic self-assemblies. Such entities, we postulate, might have had an important role in the transition from abiotic to living systems. This work should establish a completely new conceptual framework for the understanding of metabolite dynamics, association, and function and bear major implications on our understating of the origin of life.