Article ID | Journal | Published Year | Pages | File Type |
---|---|---|---|---|
2570856 | Toxicology and Applied Pharmacology | 2008 | 7 Pages |
Abstract
Indirubin, a red colored 3,2â²-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-3â²-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-3â²-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-3â²-oxime incubated with isolated rat liver mitochondria, at concentrations above 10μM, 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-3â²-oxime at up to 25μM 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-3â²-oxime significantly inhibited the activity of complex II and IV thus explaining the decreased FCCP-stimulated mitochondrial respiration. Mitochondria pre-incubated with indirubin-3â²-oxime exhibits decreased susceptibility to calcium-induced mitochondrial permeability transition. This work shows for the first time multiple effects of indirubin-3â²-oxime on mitochondrial bioenergetics thus indicating a potential mechanism for indirubin-3â²-oxime effects on cell function.
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Authors
Ana T. Varela, Ana P. Gomes, Anabela M. Simões, João S. Teodoro, Filipe V. Duarte, Anabela P. Rolo, Carlos M. Palmeira,