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Indirubin-3'-oxime Impairs Mitochondrial Oxidative Phosphorylation and Prevents Mitochondrial Permeability Transition Induction

Indirubin-3'-oxime Impairs Mitochondrial Oxidative Phosphorylation and Prevents Mitochondrial Permeability Transition Induction

Ana T Varela, Ana P Gomes, Anabela M Simões, João S Teodoro, Filipe V Duarte, Anabela P Rolo, Carlos M Palmeira

Toxicol Appl Pharmacol. 2008 Dec 1;233(2):179-85.

PMID: 18786556

Abstract:

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.

Chemicals Related in the Paper:

Catalog Number	Product Name	Structure	CAS Number	Price
AP160807498-A	Indirubin-3′-oxime		160807-49-8	Price

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