Indirubin-3'-oxime impairs mitochondrial oxidative phosphorylation and prevents mitochondrial permeability transition induction

Toxicol Appl Pharmacol. 2008 Dec 1;233(2):179-85. doi: 10.1016/j.taap.2008.08.005. Epub 2008 Aug 14.


Indirubin, a red colored 3,2'-bisindole isomer, is a component of Indigo naturalis and is an active ingredient used in traditional Chinese medicine for the treatment of chronic diseases. The family of indirubin derivatives, such as indirubin-3'-oxime, has been suggested for various therapeutic indications. However, potential toxic interactions such as indirubin effects on mitochondrial bioenergetics are still unknown. This study evaluated the action of indirubin-3'-oxime on the function of isolated rat liver mitochondria contributing to a better understanding of the biochemical mechanisms underlying the multiple effects of indirubin. Indirubin-3'-oxime incubated with isolated rat liver mitochondria, at concentrations above 10microM, significantly depresses the phosphorylation efficiency of mitochondria as inferred from the decrease in the respiratory control and ADP/O ratios, the perturbations in mitochondrial membrane potential and in the phosphorylative cycle induced by ADP. Furthermore, indirubin-3'-oxime at up to 25microM stimulates the rate of state 4 respiration and inhibits state 3 respiration. The increased lag phase of repolarization was associated with a direct inhibition of the mitochondrial ATPase. Indirubin-3'-oxime significantly inhibited the activity of complex II and IV thus explaining the decreased FCCP-stimulated mitochondrial respiration. Mitochondria pre-incubated with indirubin-3'-oxime exhibits decreased susceptibility to calcium-induced mitochondrial permeability transition. This work shows for the first time multiple effects of indirubin-3'-oxime on mitochondrial bioenergetics thus indicating a potential mechanism for indirubin-3'-oxime effects on cell function.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenosine Diphosphate / metabolism
  • Adenosine Triphosphatases / drug effects
  • Adenosine Triphosphatases / metabolism
  • Animals
  • Calcium / metabolism
  • Carbonyl Cyanide p-Trifluoromethoxyphenylhydrazone / pharmacology
  • Cell Respiration / drug effects
  • Dose-Response Relationship, Drug
  • Drugs, Chinese Herbal / chemistry
  • Indoles / administration & dosage
  • Indoles / toxicity*
  • Male
  • Membrane Potential, Mitochondrial / drug effects*
  • Mitochondria, Liver / drug effects*
  • Mitochondria, Liver / metabolism
  • Oxidative Phosphorylation / drug effects*
  • Oximes / administration & dosage
  • Oximes / toxicity*
  • Oxygen / metabolism
  • Permeability / drug effects
  • Rats
  • Rats, Wistar


  • Drugs, Chinese Herbal
  • Indoles
  • Oximes
  • indirubin-3'-monoxime
  • Carbonyl Cyanide p-Trifluoromethoxyphenylhydrazone
  • Adenosine Diphosphate
  • Adenosine Triphosphatases
  • Oxygen
  • Calcium