ArticleToxicological sciences : an official journal of the Society of Toxicology2015
Assessment of ToxCast Phase II for Mitochondrial Liabilities Using a High-Throughput Respirometric Assay.
Article in Toxicological sciences : an official journal of the Society of Toxicology, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 21 papers.
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Who cites it
21 citing papers in PubMed, 36 citations in OpenAlex.
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- Inhibition of Mitochondrial Complex III Causes Dopaminergic Neurodegeneration by Redox Stress inbioRxiv : the preprint server for biology · 2025Article
- Lack of detectable sex differences in the mitochondrial function of Caenorhabditis elegans.BMC ecology and evolution · 2024Article
- Assessing Drug-Induced Mitochondrial Toxicity in Cardiomyocytes: Implications for Preclinical Cardiac Safety Evaluation.Pharmaceutics · 2022Review
- Mapping the cellular response to electron transport chain inhibitors reveals selective signaling networks triggered by mitochondrial perturbation.Archives of toxicology · 2022Article
- Mild pentachlorophenol-mediated uncoupling of mitochondria depletes ATP but does not cause an oxidized redox state or dopaminergic neurodegeneration inCurrent research in toxicology · 2022Article
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- SAHA is neuroprotective in in vitro and in situ models of retinitis pigmentosa.Molecular vision · 2021Article
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- Respirometric Screening and Characterization of Mitochondrial Toxicants Within the ToxCast Phase I and II Chemical Libraries.Toxicological sciences : an official journal of the Society of Toxicology · 2020Article
- Age- and Organ-Specific Differences in Mitochondrial Bioenergetics in Brown Norway Rats.Journal of aging research · 2020Article
- Mitochondria as a target of organophosphate and carbamate pesticides: Revisiting common mechanisms of action with new approach methodologies.Reproductive toxicology (Elmsford, N.Y.) · 2019Article
- Linking Mitochondrial Dysfunction to Organismal and Population Health in the Context of Environmental Pollutants: Progress and Considerations for Mitochondrial Adverse Outcome Pathways.Environmental toxicology and chemistry · 2019Article
- The Next Generation Blueprint of Computational Toxicology at the U.S. Environmental Protection Agency.Toxicological sciences : an official journal of the Society of Toxicology · 2019Article
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- A high-throughput real-time in vitro assay using mitochondrial targeted roGFP for screening of drugs targeting mitochondria.Redox biology · 2019Article
- Swimming Exercise and Transient Food Deprivation in Caenorhabditis elegans Promote Mitochondrial Maintenance and Protect Against Chemical-Induced Mitotoxicity.Scientific reports · 2018Article
- Mitochondrial Toxicity.Toxicological sciences : an official journal of the Society of Toxicology · 2018Review
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- Glutaminase inhibitor CB-839 synergizes with carfilzomib in resistant multiple myeloma cells.Oncotarget · 2017Article
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Authors and funding
5 authors at 3 institutions in 1 country.
Funding
Abstract
Previous high-throughput screens to identify mitochondrial toxicants used immortalized cell lines and focused on changes in mitochondrial membrane potential, which may not be sufficient and do not identify different types of mitochondrial dysfunction. Primary cultures of renal proximal tubule cells (RPTC) were examined with the Seahorse Extracellular Flux Analyzer to screen 676 compounds (5 μM; 1 h) from the ToxCast Phase II library for mitochondrial toxicants. Of the 676 compounds, 19 were classified as cytotoxicants, 376 were electron transport chain (ETC) inhibitors, and 5 were uncouplers. The remaining 276 compounds were examined after a 5-h exposure to identify slower acting mitochondrial toxicants. This experiment identified 3 cytotoxicants, 110 ETC inhibitors, and 163 compounds with no effect. A subset of the ToxCast Phase II library was also examined in immortalized human renal cells (HK2) to determine differences in susceptibility to mitochondrial toxicity. Of the 131 RPTC ETC inhibitors tested, only 14 were ETC inhibitors in HK2 cells. Of the 5 RPTC uncouplers, 1 compound was an uncoupler in HK2 cells. These results demonstrate that 73% (491/676) of the compounds in the ToxCast Phase II library compounds exhibit RPTC mitochondrial toxicity, overwhelmingly ETC inhibition. In contrast, renal HK2 cells are markedly less sensitive and only identified 6% of the compounds as mitochondrial toxicants. We suggest caution is needed when studying mitochondrial toxicity in immortalized cell lines. This information will provide mechanisms and chemical-based criteria for assessing and predicting mitochondrial liabilities of new drugs, consumer products, and environmental agents.
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Registered trials
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