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Updated: Jan 28, 2026
Modeling Persistent Pseudomonas aeruginosa Infection in Wounded Zebrafish Larvae
Published on: June 13, 2025
Mitochondrial UPR repression during Pseudomonas aeruginosa infection requires the bZIP protein ZIP-3
Pan Deng1,2, Nandhitha Uma Naresh1, Yunguang Du1
1Department of Molecular, Cell and Cancer Biology, University of Massachusetts Medical School, Worcester, MA 01605.
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 UPRmt 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 Pseudomonas aeruginosa produces toxins that disrupt oxidative phosphorylation (OXPHOS), resulting in UPRmt activation. Here, we demonstrate that Pseudomonas aeruginosa exploits an intrinsic negative regulatory mechanism mediated by the Caenorhabditis elegans bZIP protein ZIP-3 to repress UPRmt activation. Strikingly, worms lacking zip-3 were impervious to Pseudomonas aeruginosa-mediated UPRmt repression and resistant to infection. Pathogen-secreted phenazines perturbed mitochondrial function and were the primary cause of UPRmt activation, consistent with these molecules being electron shuttles and virulence determinants. Surprisingly, Pseudomonas aeruginosa unable to produce phenazines and thus elicit UPRmt activation were hypertoxic in zip-3-deletion worms. These data emphasize the significance of virulence-mediated UPRmt repression and the potency of the UPRmt as an antibacterial response.
Insights
Pseudomonas aeruginosa infection is countered by the mitochondrial unfolded protein response (UPRmt). However, the pathogen uses ZIP-3 to suppress this defense, but its absence confers resistance.
Area of Science:
- Cellular Biology
- Infectious Disease
- Mitochondrial Biology
Background:
- Mitochondria are vital for cellular energy and are infection targets.
- Metazoans use the mitochondrial unfolded protein response (UPRmt) to detect mitochondrial dysfunction during infection.
- UPRmt is regulated by ATFS-1, promoting mitochondrial recovery and immunity.
Purpose of the Study:
- Investigate how *Pseudomonas aeruginosa* affects UPRmt.
- Identify mechanisms of UPRmt regulation during bacterial infection.
- Determine the role of ZIP-3 in *C. elegans* response to *P. aeruginosa*.
Main Methods:
- Utilized *Caenorhabditis elegans* models to study UPRmt activation and repression.
- Investigated the role of the bZIP protein ZIP-3 in regulating UPRmt.
- Analyzed the impact of *Pseudomonas aeruginosa* toxins, specifically phenazines, on mitochondrial function and UPRmt.
Main Results:
- *Pseudomonas aeruginosa* utilizes ZIP-3 to suppress UPRmt activation.
- Worms lacking *zip-3* exhibit resistance to *P. aeruginosa* infection and UPRmt repression.
- Pathogen-secreted phenazines disrupt mitochondrial function, activating UPRmt.
- Phenazine-deficient *P. aeruginosa* is hypervirulent in *zip-3* deletion worms.
Conclusions:
- *P. aeruginosa* employs virulence-mediated UPRmt repression via ZIP-3.
- UPRmt serves as a potent antibacterial response.
- Targeting ZIP-3 or enhancing UPRmt could be therapeutic strategies against *P. aeruginosa* infections.
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