Mitochondrial UPR repression during <i>Pseudomonas aeruginosa</i> infection 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 (UPR^mt) to detect and respond to mitochondrial dysfunction as an indicator of infection. The UPR^mt 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 <i>Pseudomonas aeruginosa</i> produces toxins that disrupt oxidative phosphorylation (OXPHOS), resulting in UPR^mt activation. Here, we demonstrate that <i>Pseudomonas aeruginosa</i> exploits an intrinsic negative regulatory mechanism mediated by the <i>Caenorhabditis elegans</i> bZIP protein ZIP-3 to repress UPR^mt activation. Strikingly, worms lacking <i>zip-3</i> were impervious to <i>Pseudomonas aeruginosa</i>-mediated UPR^mt repression and resistant to infection. Pathogen-secreted phenazines perturbed mitochondrial function and were the primary cause of UPR^mt activation, consistent with these molecules being electron shuttles and virulence determinants. Surprisingly, <i>Pseudomonas aeruginosa</i> unable to produce phenazines and thus elicit UPR^mt activation were hypertoxic in <i>zip-3</i>-deletion worms. These data emphasize the significance of virulence-mediated UPR^mt repression and the potency of the UPR^mt as an antibacterial response.