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

Journal Article (Journal Article)

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.

Full Text

Duke Authors

Cited Authors

  • Gonzalez-Hunt, CP; Luz, AL; Ryde, IT; Turner, EA; Ilkayeva, OR; Bhatt, DP; Hirschey, MD; Meyer, JN

Published Date

  • January 15, 2021

Published In

Volume / Issue

  • 447 /

Start / End Page

  • 152630 -

PubMed ID

  • 33188857

Pubmed Central ID

  • PMC7750303

Electronic International Standard Serial Number (EISSN)

  • 1879-3185

Digital Object Identifier (DOI)

  • 10.1016/j.tox.2020.152630

Language

  • eng

Conference Location

  • Ireland