Effects of Various Kynurenine Metabolites on Respiratory Parameters of Rat Brain, Liver and Heart Mitochondria

Abstract

Previously, we demonstrated that the endogenous glutamate receptor antagonist kynurenic acid dose-dependently and significantly affected rat heart mitochondria. Now we have investigated the effects of L-tryptophan, L-kynurenine, 3-hydroxykynurenine and kynurenic, anthranilic, 3-hydroxyanthranilic, xanthurenic and quinolinic acids on respiratory parameters (ie, state 2, state 3), respiratory control index (RC) and ADP/oxygen ratio in brain, liver and heart mitochondria of adult rats. Mitochondria were incubated with glutamate/malate (5 mM) or succinate (10 mM) and in the presence of L-tryptophan metabolites (1 mM) or in the absence, as control. Kynurenic and anthranilic acids significantly reduced RC values of heart mitochondria in the presence of glutamate/malate. Xanthurenic acid significantly reduced RC values of brain mitochondria in the presence of glutamate/malate. Furthermore, 3-hydroxykynurenine and 3-hydroxyanthranilic acid decreased RC values of brain, liver and heart mitochondria using glutamate/malate. In the presence of succinate, 3-hydroxykynurenine and 3-hydroxyanthranilic acid affected RC values of brain mitochondria, whereas in liver and heart mitochondria only 3-hydroxykynurenine lowered RC values significantly. Furthermore, lowered ADP/oxygen ratios were observed in brain mitochondria in the presence of succinate with 3-hydroxykynurenine and 3-hydroxyanthranilic acid, and to a lesser extent with glutamate/malate. In addition, 3-hydroxyanthranilic acid significantly lowered the ADP/oxygen ratio in heart mitochondria exposed to glutamate/malate, while in the liver mitochondria only a mild reduction was found. Tests of the influence of L-tryptophan and its metabolites on complex I in liver mitochondria showed that only 3-hydroxykynurenine, 3-hydroxyanthranilic acid and L-kynurenine led to a significant acceleration of NADH-driven complex I activities. The data indicate that L-tryptophan metabolites had different effects on brain, liver and heart mitochondria. Alterations of L-tryptophan metabolism might have an impact on the bioenergetic activities of brain, liver and/or heart mitochondria and might be involved in the development of clinical symptoms such as cardiomyopathy, hepatopathy and dementia.

Jerusalem Balsam Lowers Kynurenic Acid Formation: An In Vitro Study

“…Alterations of L-TRP metabolite levels in the blood found immediately after strokes indicate a significant activation of metabolism along the kynurenine pathway and increase the cardiovascular risk factor, as well [10][11][12]. In the line, we found that KYNA lowers the efficacy of mitochondria ATP synthesis of heart mitochondria [13,14].The aim of the study was to examine the Jerusalem Balsam action, whether this "natural mixture" has an ability to influence KYNA synthesis in the rat liver tissue, in an in vitro study. Subsequently we compared the effect of Jerusalem Balsam to the effect of Cerebrolysin [15] and D-cycloserine [16] in respect to inhibit KAT II activity in rat liver homogenate.…”

Impaired muscle mitochondrial energetics is associated with uremic metabolite accumulation in chronic kidney disease

“…Indole-3-acetate and l -kynurenine were recently shown to impair skeletal muscle mitochondrial ETS and select matrix dehydrogenases ( 34 ). Additionally, kynurenine and tryptophan-derived indole metabolites have been shown to decrease mitochondrial function (in vitro) in heart ( 38 , 39 ), kidney epithelial cells ( 54 ), liver ( 37 ), and skeletal muscle ( 55 ). These observations lend support to a hypothesis of uremic myopathy whereby muscle function and mitochondrial health may be related to the progressive accumulation of uremic metabolites consequent to GFR insufficiency ( 44 , 48 , 56 ).…”

“…Previous work has reported that some uremic metabolites can impair mitochondrial function (34,(37)(38)(39)(40). Based on these observations, Pearson correlation analyses were performed to identify metabolite features that were highly correlated with OXPHOS conductance (negatively and positively).…”

3‐Hydroxykynurenine and 3‐Hydroxyanthranilic Acid Enhance the Toxicity Induced by Copper in Rat Astrocyte Culture

“…Both kynurenines were able to abolish ROS production induced by copper; however, the toxic effect on mitochondrial and cellular function was enhanced by the coincubation of copper with both kynurenines. These effects may be due to the fact that both 3-HK and 3-HANA are able to affect respiratory control (oxygen consumption in states 2 and 3 of mitochondrial respiration) [ 61 ] in addition to copper toxicity in mitochondria. Both sceneries affect ATP production and can lead to cell death as can be observed in Figure 9() .…”