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

Publication ,  Journal Article
Gonzalez-Hunt, CP; Luz, AL; Ryde, IT; Turner, EA; Ilkayeva, OR; Bhatt, DP; Hirschey, MD; Meyer, JN
Published in: Toxicology
January 15, 2021

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.

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Published In

Toxicology

DOI

EISSN

1879-3185

Publication Date

January 15, 2021

Volume

447

Start / End Page

152630

Location

Ireland

Related Subject Headings

  • Uncoupling Agents
  • Toxicology
  • Rotenone
  • Oxygen Consumption
  • Mitochondria
  • Energy Metabolism
  • Electron Transport Complex I
  • Dose-Response Relationship, Drug
  • Caenorhabditis elegans
  • Animals, Genetically Modified
 

Citation

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Chicago
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Gonzalez-Hunt, C. P., Luz, A. L., Ryde, I. T., Turner, E. A., Ilkayeva, O. R., Bhatt, D. P., … Meyer, J. N. (2021). Multiple metabolic changes mediate the response of Caenorhabditis elegans to the complex I inhibitor rotenone. Toxicology, 447, 152630. https://doi.org/10.1016/j.tox.2020.152630
Gonzalez-Hunt, Claudia P., Anthony L. Luz, Ian T. Ryde, Elena A. Turner, Olga R. Ilkayeva, Dhaval P. Bhatt, Matthew D. Hirschey, and Joel N. Meyer. “Multiple metabolic changes mediate the response of Caenorhabditis elegans to the complex I inhibitor rotenone.Toxicology 447 (January 15, 2021): 152630. https://doi.org/10.1016/j.tox.2020.152630.
Gonzalez-Hunt CP, Luz AL, Ryde IT, Turner EA, Ilkayeva OR, Bhatt DP, et al. Multiple metabolic changes mediate the response of Caenorhabditis elegans to the complex I inhibitor rotenone. Toxicology. 2021 Jan 15;447:152630.
Gonzalez-Hunt, Claudia P., et al. “Multiple metabolic changes mediate the response of Caenorhabditis elegans to the complex I inhibitor rotenone.Toxicology, vol. 447, Jan. 2021, p. 152630. Pubmed, doi:10.1016/j.tox.2020.152630.
Gonzalez-Hunt CP, Luz AL, Ryde IT, Turner EA, Ilkayeva OR, Bhatt DP, Hirschey MD, Meyer JN. Multiple metabolic changes mediate the response of Caenorhabditis elegans to the complex I inhibitor rotenone. Toxicology. 2021 Jan 15;447:152630.
Journal cover image

Published In

Toxicology

DOI

EISSN

1879-3185

Publication Date

January 15, 2021

Volume

447

Start / End Page

152630

Location

Ireland

Related Subject Headings

  • Uncoupling Agents
  • Toxicology
  • Rotenone
  • Oxygen Consumption
  • Mitochondria
  • Energy Metabolism
  • Electron Transport Complex I
  • Dose-Response Relationship, Drug
  • Caenorhabditis elegans
  • Animals, Genetically Modified