Opportunities and Challenges of Overflow Metabolism in Industrial Microorganisms

Abstract Overflow metabolism represents a ubiquitous phenomenon in industrial microorganisms, characterized by the excretion of organic acids and other byproducts under aerobic, nutrient-rich conditions. While this trait enables rapid cell proliferation, it compromises the carbon utilization efficiency, impairs cellular performance, and limits industrial applicability. Traditional industrial strategies mainly focused on optimizing fermentation conditions to alleviate overflow metabolism. Recent advances have deepened our understanding of the core mechanisms underlying overflow metabolism, including carbon flux imbalance, membrane spatial crowding, protein resource allocation, and redox perturbation. This review systematically summarizes recent research progress on the underlying mechanisms of overflow metabolism as well as the targeted modification strategies developed to modulate this metabolic trait. An in-depth, multifaceted investigation of the drivers of overflow metabolism will facilitate the development of a robust microbial chassis with reduced overflow metabolism and improved bioproduction efficiency.