Overflow metabolism in bacterial, yeast, and mammalian cells: different names, same game

Overflow metabolism refers to the widespread phenomenon of cells excreting metabolic by-products into their environment. Although overflow is observed in virtually all living organisms, it has been studied independently and given different names in different species. This review highlights emerging evidence that overflow metabolism is governed by common principles in prokaryotic and eukaryotic organisms. We examine the similarities and specificities in the structure, function, and regulation of overflow pathways in bacterial, yeast, and mammalian cells, with a focus on model species and common by-products. Our reinterpretation of previous findings points to the existence of universal principles governing overflow fluxes. We also emphasize the need to reconsider the roles of overflow metabolites, not as cellular stress-inducing toxic waste, but as nutrients and regulators, influencing metabolism at both cellular and community levels, often to the benefit of the producing cells. Finally, we review prevailing theories of overflow metabolism and explore avenues toward a potential unified theory of overflow. This review offers fundamental insights into this widespread metabolic process and proposes a conceptual foundation for future research.