Mitochondrial UPR repression during infection requires the bZIP protein ZIP-3.

Mitochondria generate most cellular energy and are targeted by multiple pathogens during infection. In turn, metazoans employ surveillance mechanisms such as the mitochondrial unfolded protein response (UPR) to detect and respond to mitochondrial dysfunction as an indicator of infection. The UPR is an adaptive transcriptional program regulated by the transcription factor ATFS-1, which induces genes that promote mitochondrial recovery and innate immunity. The bacterial pathogen produces toxins that disrupt oxidative phosphorylation (OXPHOS), resulting in UPR activation. Here, we demonstrate that exploits an intrinsic negative regulatory mechanism mediated by the bZIP protein ZIP-3 to repress UPR activation. Strikingly, worms lacking were impervious to -mediated UPR repression and resistant to infection. Pathogen-secreted phenazines perturbed mitochondrial function and were the primary cause of UPR activation, consistent with these molecules being electron shuttles and virulence determinants. Surprisingly, unable to produce phenazines and thus elicit UPR activation were hypertoxic in -deletion worms. These data emphasize the significance of virulence-mediated UPR repression and the potency of the UPR as an antibacterial response.