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

• Published in: Toxicology (Amsterdam) 2021-01, Vol.447, p.152630-152630, Article 152630
• Main Authors: Gonzalez-Hunt, Claudia P., Luz, Anthony L., Ryde, Ian T., Turner, Elena A., Ilkayeva, Olga R., Bhatt, Dhaval P., Hirschey, Matthew D., Meyer, Joel N.
• Format: Article
• Language: English
• Subjects: Animals; Animals, Genetically Modified; Caenorhabditis elegans; Caenorhabditis elegans (C. elegans); Complex I; Dose-Response Relationship, Drug; Electron Transport Complex I - antagonists & inhibitors; Electron Transport Complex I - metabolism; Energy Metabolism - drug effects; Energy Metabolism - physiology; Glyoxylate; Metabolomics; Mitochondria - drug effects; Mitochondria - metabolism; Mitochondrial metabolism; Oxygen Consumption - drug effects; Oxygen Consumption - physiology; Rotenone; Rotenone - toxicity; Uncoupling Agents - toxicity
• ISSN: 0300-483X; 1879-3185
• DOI: 10.1016/j.tox.2020.152630

•Rotenone exposure resulted in metabolic shifts in Caenorhabditis elegans, allowing the nematode to maintain ATP levels.•C. elegans increased dependence on complex II and ATP synthase after rotenone, suggesting changes in how the electron transport chain was used.•Rotenone caused changes in metabolite levels consistent with upregulated glyoxylate cycle, glycolysis, and fatty acid oxidation.•Rotenone-exposed C. elegans were more sensitive to uncoupling-mediated ATP depletion, suggesting that these metabolic changes came at a cost. Rotenone, a mitochondrial complex I inhibitor, has been widely used to study the effects of mitochondrial dysfunction on dopaminergic neurons in the context of Parkinson’s disease. Although the deleterious effects of rotenone are well documented, we found that young adult Caenorhabditis elegans showed resistance to 24 and 48 h rotenone exposures. To better understand the response to rotenone in C. elegans, we evaluated mitochondrial bioenergetic parameters after 24 and 48 h exposures to 1 μM or 5 μM rotenone. Results suggested upregulation of mitochondrial complexes II and V following rotenone exposure, without major changes in oxygen consumption or steady-state ATP levels after rotenone treatment at the tested concentrations. We found evidence that the glyoxylate pathway (an alternate pathway not present in higher metazoans) was induced by rotenone exposure; gene expression measurements showed increases in mRNA levels for two complex II subunits and for isocitrate lyase, the key glyoxylate pathway enzyme. Targeted metabolomics analyses showed alterations in the levels of organic acids, amino acids, and acylcarnitines, consistent with the metabolic restructuring of cellular bioenergetic pathways including activation of complex II, the glyoxylate pathway, glycolysis, and fatty acid oxidation. This expanded understanding of how C. elegans responds metabolically to complex I inhibition via multiple bioenergetic adaptations, including the glyoxylate pathway, will be useful in interrogating the effects of mitochondrial and bioenergetic stressors and toxicants.