The UPR ^MT is a critical mediator of nutrient immunity

Mitochondria serve as critical signaling hubs that monitor the intracellular environment to orchestrate cellular stress responses during pathogen infection. The mitochondrial unfolded protein response (UPR ^MT ), a key surveillance pathway, is widely considered to be activated by pathogen-derived toxins that directly damage host mitochondria. In contrast to this prevailing model, we demonstrate that E. faecalis, which lacks specialized mitochondrial toxins, activates the UPR ^MT in C. elegans via a combination of metabolic and oxidative stress. As both C. elegans and E. faecalis are heme auxotrophs, E. faecalis -ingested animals result in severe heme deficiency, leading to the disruption of the electron transport chain and activation of the UPR ^MT . During live infection, this primary mitochondrial stress is further amplified due to the Fenton reaction, driven by host NADPH oxidase BLI-3-generated hydrogen peroxide. Ultimately, our findings position the UPR ^MT as a fundamental homeostatic sensor that monitors metabolic and oxidative imbalances at the host-pathogen interface.