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Gaining Insights into Mitochondrial Toxicity – Using Every Tool in the Box

In a previous blog entry we examined the mitochondrial respiratory complex assay and discussed the importance and role of mitochondria within the cell.  As we know, the mitochondria are common targets for drug-induced toxicity, but there are many different approaches that can assist in identifying the mechanisms by which toxic effects can occur.  Mechanisms of interest include:

  • Inhibition of mitochondrial respiration
  • Uncoupling of mitochondrial respiration from ATP synthesis
  • Alterations in the mitochondrial membrane potential (MMP)
  • Inhibition of mitochondrial membrane transporters
  • Inhibition of Krebs cycle enzymes and fatty acid metabolism
  • Inhibition of mtDNA replication and mtDNA-encoded protein synthesis
  • Mitochondrial oxidative stress
  • Mitochondrial permeability transition pore (MPTP) interference

In an effort to further understand the mechanisms of mitochondrial dysfunction, Cyprotex have investigated several different in vitro mitochondrial toxicity assays using a panel of drugs including known mitochondrial toxicants and non-toxic compounds.  We examined the following suite of mitochondrial assays:

  • Glucose/galactose cytotoxicity assay (Glu/Gal)
  • High content imaging (MMP and cytotoxicity assay)
  • Functional mitochondrial toxicity assay using the Agilent Seahorse XFe96 flux analyser (Stress test assay)
  • Permeabilised cell assay using the Agilent Seahorse XFe96 flux analyser (Respiratory complex assay)

By interrogating the sensitivity, potential throughput, and ability to identify mechanisms of toxicity, we have evaluated our current mitochondrial toolbox and determined that there are advantages in using a combined series of assays to characterise mitochondrial toxicity.

Our specialist, Senior Research Scientist Julie Eakins, presented our findings at Eurotox 2019.

To find out more:

  • Download the poster here
  • Read about our mitochondrial toxicity assays here
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