mGem: Revisiting bacterial overflow metabolism

ABSTRACT Bacterial overflow metabolism, where cells perform oxidative fermentation despite the availability of ample oxygen and carbon sources, remains a long-standing paradox in microbial metabolism. Traditional explanations attribute this phenomenon to bacterial physiology, including rapid growth, redox imbalances, competitive advantages in microbiomes, and catabolite repression. However, recent advances in systems biology have revealed additional contributing factors, such as thermodynamic constraints, proteome allocation efficiency, bioenergetics, and the membrane real estate hypothesis. Despite these insights, a comprehensive commentary that critically examines these perspectives is still lacking. In this mGem, we summarize key drivers of overflow metabolism, examine state-of-the-art theories, and identify unresolved questions in current understanding. By evaluating multiple viewpoints, we aim to provide a cohesive analysis of bacterial overflow metabolism and contribute to a broader understanding of microbial physiology, regulatory networks, and evolutionary adaptations shaping metabolic strategies.