期刊
TOXICOLOGY
卷 447, 期 -, 页码 -出版社
ELSEVIER IRELAND LTD
DOI: 10.1016/j.tox.2020.152630
关键词
Caenorhabditis elegans (C. elegans); Rotenone; Complex I; Glyoxylate; Metabolomics; Mitochondrial metabolism
资金
- Duke Cancer Institute as part of the P30 Cancer Center Support Grant [P30 CA014236]
- National Institute of Environmental Health Sciences
- National Institute of Health [R01ES017540, R01ES028218, P42ES010356]
- NIH Office of Research Infrastructure Programs [P40 OD010440]
The study found that young adult Caenorhabditis elegans showed resistance to rotenone exposure for 24 and 48 hours, with upregulation of mitochondrial complexes II and V. Results indicated that exposure to rotenone induced the glyoxylate pathway in C. elegans, along with metabolic restructuring of cellular bioenergetic pathways.
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 mu M or 5 mu M 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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