Mitochondrial UPR-regulated innate immunity provides resistance to pathogen infection

A link between an intracellular stress response, bacterial infection and triggering of the innate immune response is shown in Caenorhabditis elegans ; exposure to the pathogen Pseudomonas aeruginosa caused activation of the transcription factor ATFS-1 and innate immunity that is regulated by the mitochondrial unfolded protein response. Mitochondrial defence against bacterial pathogens The mitochondrial unfolded protein response (UPR mt ) is a stress response that activates transcription of nuclear-encoded mitochondrial chaperone genes to promote protein homeostasis within the mitochondrion. Here Mark Pellegrino et al . provide evidence that mitochondrial dysfunction, and activation of the UPR mt , leads to upregulation of innate immunity and promotes pathogen resistance in Caenorhabditis elegans exposed to Pseudomonas aeruginosa . Metazoans identify and eliminate bacterial pathogens in microbe-rich environments such as the intestinal lumen; however, the mechanisms are unclear. Host cells could potentially use intracellular surveillance or stress response programs to detect pathogens that target monitored cellular activities and then initiate innate immune responses 1 , 2 , 3 . Mitochondrial function is evaluated by monitoring mitochondrial protein import efficiency of the transcription factor ATFS-1, which mediates the mitochondrial unfolded protein response (UPR mt ). During mitochondrial stress, mitochondrial import is impaired 4 , allowing ATFS-1 to traffic to the nucleus where it mediates a transcriptional response to re-establish mitochondrial homeostasis 5 . Here we examined the role of ATFS-1 in Caenorhabditis elegans during pathogen exposure, because during mitochondrial stress ATFS-1 induced not only mitochondrial protective genes but also innate immune genes that included a secreted lysozyme and anti-microbial peptides. Exposure to the pathogen Pseudomonas aeruginosa caused mitochondrial dysfunction and activation of the UPR mt . C. elegans lacking atfs-1 were susceptible to P. aeruginosa, whereas hyper-activation of ATFS-1 and the UPR mt improved clearance of P. aeruginosa from the intestine and prolonged C. elegans survival in a manner mainly independent of known innate immune pathways 6 , 7 . We propose that ATFS-1 import efficiency and the UPR mt is a means to detect pathogens that target mitochondria and initiate a protective innate immune response.