Kynurenic Acid Influences the Respiratory Parameters of Rat Heart Mitochondria

Baran, Halina; Staniek, Katrin; Kepplinger, Berthold; Gille, Lars; Stolze, Klaus; Nohl, Hans

doi:10.1159/000056082

Cited by 33 publications

(33 citation statements)

References 23 publications

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“…This is in agreement with previous reports showing that cellular respiration is altered by kynurenines (Baran et al, 2001(Baran et al, , 2003 and possibly explain the mechanisms by which the metabolites affect the mitochondrial respiration.…”

Section: Discussionsupporting

confidence: 93%

“…This is interesting since some enzymes that catalyze the kynurenine pathway are located in the inner membrane of the mitochondria or inside this organelle, implying that kynurenines may have a direct and/or an indirect effect on the mitochondrial bioenergetics (Brown, 1971;Okamoto, 1971;Bender and McCreanor, 1982). Baran et al (2001) demonstrated that kynurenic acid (KA) affected dose-dependently the respiratory parameters of heart mitochondria, reducing significantly the respiratory control and P/O values. Furthermore, 3HK and 3HA lowered the respiratory control index and the ADP/oxygen ratio in the presence of glutamate/malate and succinate, while anthranilic acid (AA) reduced state III oxygen comsumption rate and lowered the respiratory control index only of glutamate/malate-respiring heart mitochondria (Baran et al, 2003).…”

Section: Discussionmentioning

confidence: 99%

“…However, mitochondrial respiratory parameters have been demonstrated to be altered by some kynurenines (Baran et al, 2001(Baran et al, , 2003. Interestingly, various studies have shown that impairment of mitochondrial function, evidenced by inhibition of the mitochondrial respiratory chain, decreased cerebral glucose utilization and reduction of oxygen consumption, is considered an important pathomechanism in some neurodegenerative disorders (Coyle and Puttfarcken, 1993;Cassarino and Bennet, 1999).…”

Section: Introductionmentioning

confidence: 99%

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Kynurenines Impair Energy Metabolism in Rat Cerebral Cortex

et al. 2006

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Growing evidence indicates that some metabolites derived from the kynurenine pathway, the major route of L-tryptophan catabolism, are involved in the neurotoxicity associated with several brain disorders, such as Huntington's disease, Parkinson's disease and Alzheimer's disease, as well as in glutaryl-CoA dehydrogenase deficiency (GAI). Considering that the pathophysiology of the brain damage in these neurodegenerative disorders is not completely defined, in the present study, we investigated the in vitro effect of L-kynurenine (Kyn), kynurenic acid (KA), 3-hydroxykynurenine (3HK), 3-hydroxyanthranilic acid (3HA) and anthranilic acid (AA) on some parameters of energy metabolism, namely glucose uptake, 14CO2 production from [U-14C] glucose, [1-14C] acetate and [1,5-14C] citrate, as well as on the activities of the respiratory chain complexes I-IV and Na+,K+-ATPase activity in cerebral cortex from 30-day-old rats. We observed that all compounds tested, except L-kynurenine, significantly increased glucose uptake and inhibited 14CO2 production from [U-14C] glucose, [1-14C] acetate and [1,5-14C] citrate. In addition, the activities of complexes I, II and IV of the respiratory chain were significantly inhibited by 3HK, while 3HA inhibited complexes I and II activities and AA inhibited complexes I-III activities. Moreover, Na+,K+-ATPase activity was not modified by these kynurenines. Taken together, our present data provide evidence that various kynurenine intermediates provoke impairment of brain energy metabolism.

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Section: Discussionsupporting

confidence: 93%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Kynurenines Impair Energy Metabolism in Rat Cerebral Cortex

et al. 2006

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“…On the other hand, the observed changes may be also a result of the KYNA effect on cancer cell metabolism. Previous studies revealed that KYNA decreased ATP synthesis in the presence of glutamate and malate in mitochondria isolated from rat heart (Baran et al 2001). …”

Section: Discussionmentioning

confidence: 91%

Kynurenic acid inhibits colon cancer proliferation in vitro: effects on signaling pathways

2014

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Kynurenic acid (KYNA), a tryptophan metabolite, inhibits proliferation of several cancer cell lines including colon cancer, renal cancer and glioblastoma cells. Previous studies reported that inhibitory properties of KYNA may be related to interactions of KYNA with cell cycle regulators and signaling proteins. However, the exact molecular interaction of KYNA with signaling pathways in colon cancer cells has not been studied to date. The molecular mechanism of KYNA activity towards colon cancer cells may be of great importance taking into consideration that KYNA is present in several tissues and physiological fluids, including gastrointestinal tract, and it is also present in various products of human diet. In this study, the inhibitory effect of KYNA on activation of phosphoinositide 3-kinase/Akt (PI3K/Akt) and mitogen-activated protein kinase (MAPK) signaling pathways in colon adenocarcinoma HT-29 cells was revealed. KYNA decreased phosphorylation of Akt, ERK 1/2 and p38 kinases in HT-29 cells. Interestingly, the study revealed also unexpected effect of KYNA on Wnt pathway in HT-29 cells. KYNA in millimolar concentrations increased protein expression of β-catenin. However, the nuclear translocation of β-catenin in HT-29 cells exposed to KYNA was not observed. Moreover, KYNA 1 mM increased antiproliferative properties of inhibitors of signaling pathways: wortmannin, PD98059, SB202190 and IWR-1. Taking into consideration these results, KYNA may be seen as a potential chemopreventive agent in colon cancer or supportive agent in standard cancer chemotherapy. However, the interactions between KYNA, Wnt signaling pathway and β-catenin need further studies to exclude potential effect of KYNA on colon carcinogenesis.

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“…The toxicity of KYNA reported by other authors differed, depending on the used cell model, although the level of toxic concentrations was always higher by a few hundred-or even a few thousand-fold than values of KYNA detected in the human organism during the course of an inflammatory process. The adverse influence of KYNA on functions of the rat's myocardial mitochondria was observed at the concentrations of 125 μM -10 mM/l (Baran et al 2001), whereas the proliferation of endothelial cells in the bovine aorta was decreased (by 25%) at the concentration of 1 mM (Wejksza et al 2009). The mixed culture of rainbow trout lymphocytes employed in our study was characterized by a yet lower sensitivity to the adverse effect of high KYNA concentrations.…”

Section: Discussionmentioning

confidence: 95%

The in vitro effect of kynurenic acid on the rainbow trout (Oncorhynchus mykiss) leukocyte and splenocyte activity

Małaczewska¹,

Siwicki²,

Wójcik³

et al. 2014

Polish Journal of Veterinary Sciences

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Kynurenic acid (KYNA), an endogenous neuroprotectant formed along the kynurenine pathway of tryptophan degradation, is a selective ligand of the GPR35 receptor, which can be found on the surface of various populations of human immune cells. In infections and inflammations, KYNA produces an anti-inflammatory effect through this receptor, by depressing the synthesis of reactive oxygen species and pro-inflammatory cytokines. However, it is still unrecognized whether receptors for kynurenic acid are also localized on immune cells of poikilothermic animals, or whether KYNA is able to affect these cells. The objective of this study has been to determine the effect of different concentrations of kynurenic acid (12.5 μM to 10 mM) on the viability and mitogenic response of lymphocytes and on the activity of phagocytic cells isolated from blood and the spleen of rainbow trout. The results imply low toxicity of kynurenic acid towards fish immune cells, and the proliferative effect observed at the two lowest concentrations of KYNA (12.5 μM and 25 μM) seems indicative of endogenous kynurenic acid being capable of activating fish lymphocytes. Non-toxic, micromole concentrations of KYNA, however, had no influence on the mitogenic response of lymphocytes nor on the activity of phagocytes in rainbow trout under in vitro conditions. There is some likelihood that such an effect could be observed at lower, nanomole concentrations of KYNA.

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Kynurenic Acid Influences the Respiratory Parameters of Rat Heart Mitochondria

Cited by 33 publications

References 23 publications

Kynurenines Impair Energy Metabolism in Rat Cerebral Cortex

Kynurenines Impair Energy Metabolism in Rat Cerebral Cortex

Kynurenic acid inhibits colon cancer proliferation in vitro: effects on signaling pathways

The in vitro effect of kynurenic acid on the rainbow trout (Oncorhynchus mykiss) leukocyte and splenocyte activity

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