Abstract
Bacterial energy-spilling pathways-such as overflow metabolism and futile cycles-have been considered inefficient forms of metabolism that result from poor regulatory control or function as mechanisms to cope with excess energy. However, mounting evidence places these seemingly wasteful reactions at the fulcrum between metabolic signaling and stress adaptation in bacteria. Specifically, energy-spilling pathways may mediate the metabolic reprogramming observed when cells encounter growth-limiting constraints (i.e., nutrient limitation). Recent insights spotlight microbial metabolism as an intricate signaling network that coordinates physiological programming with energy and nutrient conditions. Such intracellular metabolic cross stalk is pivotal to survival in competitive, fluctuating environments that bacteria frequently encounter in nature. In light of this paradigm of metabolic signaling, energy-spilling pathways are increasingly recognized as regulatory strategies that enable metabolic rewiring in response to stress. Overflow metabolism or futile cycles may generate secondary metabolites with signaling properties, alter the flux of metabolic pathways and the rate of nutrient acquisition, or stimulate regulatory nodes to trigger specific metabolic programs in response to environmental challenges. Furthermore, the observation of such expensive pathways under laboratory conditions purported to be "energy limiting" may in fact suggest energy sufficiency, compelling us to rethink how we model energy limitation and starvation for bacteria.