Mitochondrial UPR repression duringPseudomonas aeruginosainfection requires the bZIP protein ZIP-3

Abstract

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 (UPRmt) to detect and respond to mitochondrial dysfunction as an indicator of infection. The UPRmtis an adaptive transcriptional program regulated by the transcription factor ATFS-1, which induces genes that promote mitochondrial recovery and innate immunity. The bacterial pathogenPseudomonas aeruginosaproduces toxins that disrupt oxidative phosphorylation (OXPHOS), resulting in UPRmtactivation. Here, we demonstrate thatPseudomonas aeruginosaexploits an intrinsic negative regulatory mechanism mediated by theCaenorhabditis elegansbZIP protein ZIP-3 to repress UPRmtactivation. Strikingly, worms lackingzip-3were impervious toPseudomonas aeruginosa-mediated UPRmtrepression and resistant to infection. Pathogen-secreted phenazines perturbed mitochondrial function and were the primary cause of UPRmtactivation, consistent with these molecules being electron shuttles and virulence determinants. Surprisingly,Pseudomonas aeruginosaunable to produce phenazines and thus elicit UPRmtactivation were hypertoxic inzip-3–deletion worms. These data emphasize the significance of virulence-mediated UPRmtrepression and the potency of the UPRmtas an antibacterial response.