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Rotenone Modulates Caenorhabditis elegans Immunometabolism and Pathogen Susceptibility
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International audience. Mitochondria are central players in host immunometabolism as they function not only asmetabolic hubs but also as signaling platforms regulating innate immunity. Environmentalexposures to mitochondrial toxicants occur widely and are increasingly frequent.Exposures to these mitotoxicants may pose a serious threat to organismal health andthe onset of diseases by disrupting immunometabolic pathways. In this study, weinvestigated whether the Complex I inhibitor rotenone could alter C. elegansimmunometabolism and disease susceptibility. C. elegans embryos were exposed torotenone (0.5 μM) or DMSO (0.125%) until they reached the L4 larval stage. Inhibition ofmitochondrial respiration by rotenone and disruption of mitochondrial metabolism wereevidenced by rotenone-induced detrimental effects on mitochondrial efficiency andnematode growth and development. Next, through transcriptomic analysis, weinvestigated if this specific but mild mitochondrial stress that we detected would lead tothe modulation of immunometabolic pathways. We found 179 differentially expressedgenes (DEG), which were mostly involved in detoxification, energy metabolism, andpathogen defense. Interestingly, among the down-regulated DEG, most of the knowngenes were involved in immune defense, and most of these were identified as commonlyupregulated during P. aeruginosa infection. Furthermore, rotenone increasedsusceptibility to the pathogen Pseudomonas aeruginosa (PA14). However, it increasedresistance to Salmonella enterica (SL1344). To shed light on potential mechanisms relatedto these divergent effects on pathogen resistance, we assessed the activation of themitochondrial unfolded protein response (UPR mt ), a well-known immunometabolicpathway in C. elegans which links mitochondria and immunity and provides resistanceto pathogen infection. The UPR mt pathway was activated in rotenone-treated nematodesfurther exposed for 24 h to the pathogenic bacteria P. aeruginosa and S. enterica or thecommon bacterial food source Escherichia coli (OP50). However, P. aeruginosa alonesuppressed UPRmt activation and rotenone treatment rescued its activation only to thelevel of DMSO-exposed nematodes fed with E. coli. Module-weighted annotationbioinformatics analysis was also consistent with UPR mt activation in rotenone-exposednematodes consistent with the UPR being involved in the increased resistance to S enterica. Together, our results demonstrate that the mitotoxicant rotenone can disrupt C.elegans immunometabolism in ways likely protective against some pathogen species butsensitizing against others.
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