Abstract
The mitochondrial unfolded protein response (UPRmt) is a stress-activated pathway promoting mitochondrial recovery and defense against infection. In C. elegans, the UPRmt is activated during infection with the pathogen Pseudomonas aeruginosa—but only transiently. As this may reflect a pathogenic strategy to target a pathway required for host survival, we conducted a P. aeruginosa genetic screen to uncover mechanisms associated with this temporary activation. Here, we find that loss of the P. aeruginosa acyl-CoA dehydrogenase FadE2 prolongs UPRmt activity and extends host survival. FadE2 shows substrate preferences for the coenzyme A intermediates produced during the breakdown of the branched-chain amino acids valine and leucine. Our data suggests that during infection, FadE2 restricts the supply of these catabolites to the host hindering host energy metabolism in addition to the UPRmt. Thus, a metabolic pathway in P. aeruginosa contributes to pathogenesis during infection through manipulation of host energy status and mitochondrial stress signaling potential.
Highlights
Mitochondria supply cellular energy in the form of ATP through the actions of the tricarboxylic acid (TCA) cycle and oxidative phosphorylation (OXPHOS)
The mitochondrial unfolded protein response (UPRmt) is classically involved in resolving mitochondrial dysfunction but is necessary to protect the host during infection with bacterial pathogens such as Pseudomonas aeruginosa
We find that the novel P. aeruginosa acyl-CoA dehydrogenase FadE2, involved in the catabolism of the branched-chain amino acids valine and leucine, is associated with the repression of the UPRmt that limits host survival
Summary
Mitochondria supply cellular energy in the form of ATP through the actions of the tricarboxylic acid (TCA) cycle and oxidative phosphorylation (OXPHOS). Cells use a variety of mechanisms to mitigate mitochondrial stress including the mitochondrial unfolded protein response (UPRmt) [1,2,3]. The UPRmt is activated during stress in order to help restore mitochondrial homeostasis through the transcriptional regulation of a variety of protective genes. In C. elegans, the bZIP transcription factor ATFS-1 mediates the UPRmt and is regulated by mitochondrial import efficiency [4, 5]. ATFS-1 contains a mitochondrial targeting sequence and is imported into healthy mitochondria where it is turned over via protease-mediated degradation. ATFS-1 accumulates cytoplasmically during mitochondrial stress and, because it has a nuclear localization sequence, is imported into the nucleus to transcriptionally regulate a diverse set of genes which promote mitochondrial recovery [5]
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