Multiple metabolic changes mediate the response of Caenorhabditis elegans to the complex I inhibitor rotenone

Gonzalez‐Hunt, Claudia P.; Luz, Anthony L.; Ryde, Ian T.; Turner, Elena A.; Bhatt, Dhaval P.; Hirschey, Matthew D.; Meyer, Joel N.

doi:10.1016/j.tox.2020.152630

Cited by 15 publications

(14 citation statements)

References 67 publications

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“…Most of the DEG associated with energy metabolism were up-regulated and annotated as involved in fatty acid β-oxidation ( Figure 4C ). This result is consistent with a previous study from our group which also detected, through metabolomics analysis, increased fatty acid β-oxidation in adult nematodes exposed to rotenone ( 39 ). This increase might be related to a need to replenish acetyl-CoA levels or to boost ATP production upon Complex I inhibition, although the latter hypothesis was not confirmed in our previous work ( 39 ).…”

Section: Discussionsupporting

confidence: 93%

“…This result is consistent with a previous study from our group which also detected, through metabolomics analysis, increased fatty acid β-oxidation in adult nematodes exposed to rotenone ( 39 ). This increase might be related to a need to replenish acetyl-CoA levels or to boost ATP production upon Complex I inhibition, although the latter hypothesis was not confirmed in our previous work ( 39 ). Fatty acid β-oxidation plays a significant role in immunometabolism.…”

Section: Discussionsupporting

confidence: 93%

“…Previous studies from our research group and data from the literature show that different classes of toxicants can promote physiological stress in organisms by changing energy metabolism (14,(38)(39)(40)(41) and innate immune responses (1-7, 42-48). However, although the fields of immunometabolism and mitoimmunity have recently been the focus of extensive research, most studies use vertebrate models, and little attention is directed to mitoimmune dysfunction in the context of pollutant exposures.…”

Section: Discussionmentioning

confidence: 98%

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Rotenone Modulates Caenorhabditis elegans Immunometabolism and Pathogen Susceptibility

et al. 2022

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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.

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Section: Discussionsupporting

confidence: 93%

Section: Discussionsupporting

confidence: 93%

Section: Discussionmentioning

confidence: 98%

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Rotenone Modulates Caenorhabditis elegans Immunometabolism and Pathogen Susceptibility

et al. 2022

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“…others demonstrating that upregulation of mitochondrial complexes II and V (following rotenone exposure) did not lead to major changes in oxygen consumption or steady-state ATP levels. 40 On the other hand, the insignificant effect of CCCP (Figure 6) or FCCP (Figure 4) in ju71 on observed parameters might reveal poor maintenance of proton gradients (or lack of necessity to maintain proper proton gradient).…”

Section: Discussionmentioning

confidence: 93%

“…Worms were then mounted onto 2% agarose pads for imaging. Drug treatments were performed as described in References 40,52. The complex V inhibitor oligomycin (Sigma‐Adrich #579‐13‐5), a mitochondrial oxidative phosphorylation uncoupler carbonyl cyanide m‐chlorophenylhydrazone (CCCP) (Sigma‐Adrich #555‐60‐2), and a mitochondrial complex I inhibitor, rotenone (Rot) (Sigma‐Adrich #83‐79‐4) were dissolved in DMSO and added to reach the target concentrations (1 nM oligomycin, 20 μM CCCP and 5 μM rotenone) on NGM plates.…”

Section: Methodsmentioning

confidence: 99%

Loss of intermediate filament IFB‐1 reduces mobility, density, and physiological function of mitochondria in Caenorhabditis elegans sensory neurons

Barmaver

Shanmugam

Chang

et al. 2022

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Mitochondria and intermediate filament (IF) accumulations often occur during imbalanced axonal transport leading to various types of neurological diseases. It is still poorly understood whether a link between neuronal IFs and mitochondrial mobility exist. In Caenorhabditis elegans, among the 11 cytoplasmic IF family proteins, IFB‐1 is of particular interest as it is expressed in a subset of sensory neurons. Depletion of IFB‐1 leads to mild dye‐filling and significant chemotaxis defects as well as reduced life span. Sensory neuron development is affected and mitochondrial transport is slowed down leading to reduced densities of these organelles. Mitochondria tend to cluster in neurons of IFB‐1 mutants likely independent of the fission and fusion machinery. Oxygen consumption and mitochondrial membrane potential is measurably reduced in worms carrying mutations in the ifb‐1 gene. Membrane potential also seems to play a role in transport such as carbonyl cyanide p‐(trifluoromethoxy)phenylhydrazone treatment led to increased directional switching of mitochondria. Mitochondria co‐localize with IFB‐1 in worm neurons and appear in a complex with IFB‐1 in pull‐down assays. In summary, we propose a model in which neuronal IFs may serve as critical (transient) anchor points for mitochondria during their long‐range transport in neurons for steady and balanced transport.

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Metabolomics in neurodegenerative disorders—Parkinson’s disease

Gupta,

Bhaduri,

Dixit

2024

Comprehensive Analytical Chemistry

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Multiple metabolic changes mediate the response of Caenorhabditis elegans to the complex I inhibitor rotenone

Cited by 15 publications

References 67 publications

Rotenone Modulates Caenorhabditis elegans Immunometabolism and Pathogen Susceptibility

Rotenone Modulates Caenorhabditis elegans Immunometabolism and Pathogen Susceptibility

Loss of intermediate filament IFB‐1 reduces mobility, density, and physiological function of mitochondria in Caenorhabditis elegans sensory neurons

Metabolomics in neurodegenerative disorders—Parkinson’s disease

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