Rotenone Modulates Caenorhabditis elegans Immunometabolism and Pathogen Susceptibility

Abstract

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 C. elegans immunometabolism and disease susceptibility. C. elegans 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 P. aeruginosa infection. Furthermore, rotenone increased susceptibility to the pathogen Pseudomonas aeruginosa (PA14). However, it increased resistance to Salmonella enterica (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 (UPRmt), a well-known immunometabolic pathway in C. elegans which links mitochondria and immunity and provides resistance to pathogen infection. The UPRmt pathway was activated in rotenone-treated nematodes further exposed for 24 h to the pathogenic bacteria P. aeruginosa and S. enterica or the common bacterial food source Escherichia coli (OP50). However, P. aeruginosa alone suppressed UPRmt activation and rotenone treatment rescued its activation only to the level of DMSO-exposed nematodes fed with E. coli. Module-weighted annotation bioinformatics analysis was also consistent with UPRmt activation in rotenone-exposed nematodes 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 but sensitizing against others.

An unbiased, automated platform for scoring dopaminergic neurodegeneration inC. elegans

“…Interestingly, AUDDIT revealed that worms exposed to 0.03 µM rotenone have shorter dendrites than controls (Fig 3C). We hypothesize that this is due to rotenone slowing development in worms, and thus making the dendrites shorter(46). The worms exposed to 0.5 µM rotenone were grown for an extra day to account for slower development, which permitted the dendrites enough time to reach the same length as the controls.…”

Activation of innate immunity selectively compromises mitochondrial complex I, proline oxidation and flight activity in the major arbovirus vectorAedes aegypti

“…Remarkably, a shift towards G3P and succinate oxidation was observed suggesting that functional suppression complex I-dependent OXPHOS is linked to immune activation (Cormier et al, 2022). In C. elegans, while strong inhibition of complex I activates innate immune response and prevents neurodegeneration (Chikka et al, 2016), mild rotenone treatment down-regulated the expression of immune response genes, rendering roundworms prone to bacterial infections (Mello et al, 2022). In summary, we demonstrate that activation of innate immunity is strongly associated with reduced flight muscle complex I activity with direct consequences to mitochondrial proline oxidation and flight activity.…”

“…From the evolutive perspective, functional associations between complex I and immunity were reported for invertebrate organisms (Chikka et al, 2016; Cormier et al, 2022; Mello et al, 2022). In this sense, specific complex I-driven OXPHOS associates with increasing defensin expression in honeybees during winter (Cormier et al, 2022).…”

β-Carbolines norharman and harman change neurobehavior causing neurological damage in Caenorhabditis elegans

“…It was suggested that norharman and harman could disturb the metabolism of compounds in nematodes by changing the expressions of genes that regulate the key enzymes in phase II reactions, ultimately inducing neurotoxicity. 42…”