Rotenone Modulates Immunometabolism and Pathogen Susceptibility

Mitochondria are central players in host immunometabolism as they function not only as metabolic hubs but also as signaling platforms regulating innate immunity. Environmental exposures to mitochondrial toxicants occur widely and are increasingly frequent. Exposures to these mitotoxicants may pose a serious threat to organismal health and the onset of diseases by disrupting immunometabolic pathways. In this study, we investigated whether the Complex I inhibitor rotenone could alter immunometabolism and disease susceptibility. embryos were exposed to rotenone (0.5 µM) or DMSO (0.125%) until they reached the L4 larval stage. Inhibition of mitochondrial respiration by rotenone and disruption of mitochondrial metabolism were evidenced by rotenone-induced detrimental effects on mitochondrial efficiency and nematode growth and development. Next, through transcriptomic analysis, we investigated if this specific but mild mitochondrial stress that we detected would lead to the modulation of immunometabolic pathways. We found 179 differentially expressed genes (DEG), which were mostly involved in detoxification, energy metabolism, and pathogen defense. Interestingly, among the down-regulated DEG, most of the known genes were involved in immune defense, and most of these were identified as commonly upregulated during infection. Furthermore, rotenone increased susceptibility to the pathogen (PA14). However, it increased resistance to (SL1344). To shed light on potential mechanisms related to these divergent effects on pathogen resistance, we assessed the activation of the mitochondrial unfolded protein response (UPR), a well-known immunometabolic pathway in which links mitochondria and immunity and provides resistance to pathogen infection. The UPR pathway was activated in rotenone-treated nematodes further exposed for 24 h to the pathogenic bacteria and or the common bacterial food source (OP50). However, alone suppressed UPR activation and rotenone treatment rescued its activation only to the level of DMSO-exposed nematodes fed with . Module-weighted annotation bioinformatics analysis was also consistent with UPR activation in rotenone-exposed nematodes consistent with the UPR being involved in the increased resistance to . Together, our results demonstrate that the mitotoxicant rotenone can disrupt immunometabolism in ways likely protective against some pathogen species but sensitizing against others.