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1. Mitochondrial respiratory states and rate

Author

Gnaiger, E., Aasander Frostner, E., Abdul Karim, N., Abumrad, NA., Acuna-Castroviejo, D., Adiele, RC., Ahn, B., Ali, SS., Alton, L., Alves, MG., Amati, F., Amoedo, ND., Andreadou, I., Arago, M., Aral, C., Arandarcikaite, O., Armand, AS., Arnould, T., Avram, VF., Bailey, DM., Bajpeyi, S., Bajzikova, M., Bakker, BM., Barlow, J., Bastos Sant'Anna Silva, AC., Batterson, P., Battino, M., Bazil, J., Beard, DA., Bednarczyk, P., Bello, F., Ben-Shachar, D., Bergdahl, A., Berge, RK., Bergmeister, L., Bernardi, P., Berridge, MV., Bettinazzi, S., Bishop, D., Blier, PU., Blindheim, DF., Boardman, NT., Boetker, HE., Borchard, S., Boros, M., Borsheim, E., Borutaite, V., Botella, J., Bouillaud, F., Bouitbir, J., Boushel, RC., Bovard, J., Breton, S., Brown, DA., Brown, GC., Brown, RA., Brozinick, JT., Buettner, GR., Burtscher, J., Calabria, E., Calbet, JA., Calzia, E., Cannon, DT., Cano Sanchez, M., Canto, AC., Cardoso, LHD., Carvalho, E., Casado Pinna, M., Cassar, S., Cassina, AM., Castelo, MP., Castro, L., Cavalcanti-de-Albuquerque, JP., Cervinkova, Z., Chabi, B., Chakrabarti, L., Chakrabarti, S., Chaurasia, B., Chen, Q., Chicco, AJ., Chinopoulos, C., Chowdhury, SK., Cizmarova, B., Clementi, E., Coen, PM., Cohen, BH., Coker, RH., Collin, A., Crisostomo, L., Dahdah, N., Dalgaard, LT., Dambrova, M., Danhelovska, T., Darveau, CA., Das, AM., Dash, RK., Davidova, E., Davis, MS., De Goede, P., De Palma, C., Dembinska-Kiec, A., Detraux, D., Devaux, Y., Di Marcello, M., Dias, TR., Distefano, G., Doermann, N., Doerrier, C., Dong, L., Donnelly, C., Drahota, Z., Duarte, FV., Dubouchaud, H., Duchen, MR., Dumas, JF., Durham, WJ., Dymkowska, D., Dyrstad, SE., Dyson, A., Dzialowski, EM., Eaton, S., Ehinger, J., Elmer, E., Endlicher, R., Engin, AB., Escames, G., Ezrova, Z., Falk, MJ., Fell, DA., Ferdinandy, P., Ferko, M., Ferreira, JCB., Ferreira, R., Ferri, A., Fessel, JP., Filipovska, A., Fisar, Z., Fischer, C., Fischer, M., Fisher, G., Fisher, JJ., Ford, E., Fornaro, M., Galina, A., Galkin, A., Gallee, L., Galli, GL., Gama Perez, P., Gan, Z., Ganetzky, R., Garcia-Rivas, G., Garcia-Roves, PM., Garcia-Souza, LF., Garipi, E., Garlid, KD., Garrabou, G., Garten, A., Gastaldelli, A., Gayen, J., Genders, AJ., Genova, ML., Giovarelli, M., Goncalo Teixeira da Silva, R., Goncalves, DF., Gonzalez-Armenta, JL., Gonzalez-Freire, M., Gonzalo, H., Goodpaster, BH., Gorr, TA., Gourlay, CW., Granata, C., Grefte, S., Guarch, ME., Gueguen, N., Gumeni, S., Haas, CB., Haavik, J., Haendeler, J., Haider, M., Hamann, A., Han, J., Han, WH., Hancock, CR., Hand, SC., Handl, J., Hargreaves, IP., Harper, ME., Harrison, DK., Hassan, H., Hausenloy, DJ., Heales, SJR., Heiestad, C., Hellgren, KT., Hepple, RT., Hernansanz-Agustin, P., Hewakapuge, S., Hickey, AJ., Ho, DH., Hoehn, KL., Hoel, F., Holland, OJ., Holloway, GP., Hoppel, CL., Hoppel, F., Houstek, J., Huete-Ortega, M., Hyrossova, P., Iglesias-Gonzalez, J., Irving, BA., Isola, R., Iyer, S., Jackson, CB., Jadiya, P., Jana, PF., Jang, DH., Jang, YC., Janowska, J., Jansen, K., Jansen-Duerr, P., Jansone, B., Jarmuszkiewicz, W., Jaskiewicz, A., Jedlicka, J., Jespersen, NR., Jha, RK., Jurczak, MJ., Jurk, D., Kaambre, T., Kaczor, JJ., Kainulainen, H., Kampa, RP., Kandel, SM., Kane, DA., Kapferer, W., Kappler, L., Karabatsiakis, A., Karavaeva, I., Karkucinska-Wieckowska, A., Kaur, S., Keijer, J., Keller, MA., Keppner, G., Khamoui, AV., Kidere, D., Kilbaugh, T., Kim, HK., Kim, JKS., Klepinin, A., Klepinina, L., Klingenspor, M., Klocker, H., Komlodi, T., Koopman, WJH., Kopitar-Jerala, N., Kowaltowski, AJ., Kozlov, AV., Krajcova, A., Krako Jakovljevic, N., Kristal, BS., Krycer, JR., Kuang, J., Kucera, O., Kuka, J., Kwak, HB., Kwast, K., Laasmaa, M., Labieniec-Watala, M., Lagarrigue, S., Lai, N., Land, JM., Lane, N., Laner, V., Lanza, IR., Laranjinha, J., Larsen, TS., Lavery, GG., Lazou, A., Lee, HK., Leeuwenburgh, C., Lehti, M., Lemieux, H., Lenaz, G., Lerfall, J., Li, PA., Li Puma, L., Liepins, E., Liu, J., Lopez, LC., Lucchinetti, E., Ma, T., Macedo, MP., Maciej, S., MacMillan-Crow, LA., Majtnerova, P., Makarova, E., Makrecka-Kuka, M., Malik, AN., Markova, M., Martin, DS., Martins, AD., Martins, JD., Maseko, TE., Maull, F., Mazat, JP., McKenna, HT., McKenzie, M., Menze, MA., Merz, T., Meszaros, AT., Methner, A., Michalak, S., Moellering, DR., Moisoi, N., Molina, AJA., Montaigne, D., Moore, AL., Moreau, K., Moreira, BP., Moreno-Sanchez, R., Mracek, T., Muccini, AM., Munro, D., Muntane, J., Muntean, DM., Murray, AJ., Musiol, E., Nabben, M., Nair, KS., Nehlin, JO., Nemec, M., Neufer, PD., Neuzil, J., Neviere, R., Newsom, SA., Nozickova, K., O'Brien, KA., O'Gorman, D., Olgar, Y., Oliveira, B., Oliveira, MF., Oliveira, MT., Oliveira, PF., Oliveira, PJ., Orynbayeva, Z., Osiewacz, HD., Pak, YK., Pallotta, ML., Palmeira, CM., Parajuli, N., Passos, JF., Passrugger, M., Patel, HH., Pavlova, N., Pecina, P., Pedersen, TM., Pereira da Silva Grilo da Silva, F., Pereira, SP., Perez Valencia, JA., Perks, KL., Pesta, D., Petit, PX., Pettersen, IKN., Pichaud, N., Pichler, I., Piel, S., Pietka, TA., Pino, MF., Pirkmajer, S., Plangger, M., Porter, C., Porter, RK., Procaccio, V., Prochownik, EV., Prola, A., Pulinilkunnil, T., Puskarich, MA., Puurand, M., Radenkovic, F., Ramzan, R., Rattan, SIS., Reboredo, P., Renner-Sattler, K., Rial, E., Robinson, MM., Roden, M., Rodriguez, E., Rodriguez-Enriquez, S., Roesland, GV., Rohlena, J., Rolo, AP., Ropelle, ER., Rossignol, R., Rossiter, HB., Rubelj, I., Rybacka-Mossakowska, J., Saada, A., Safaei, Z., Saharnaz, S., Salin, K., Salvadego, D., Sandi, C., Saner, N., Sanz, A., Sazanov, LA., Scatena, R., Schartner, M., Scheibye-Knudsen, M., Schilling, JM., Schlattner, U., Schoenfeld, P., Schots, PC., Schulz, R., Schwarzer, C., Scott, GR., Selman, C., Shabalina, IG., Sharma, P., Sharma, V., Shevchuk, I., Shirazi, R., Shiroma, JG., Siewiera, K., Silber, AM., Silva, AM., Sims, CA., Singer, D., Singh, BK., Skolik, R., Smenes, BT., Smith, J., Soares, FAA., Sobotka, O., Sokolova, I., Sonkar, VK., Sowton, AP., Sparagna, GC., Sparks, LM., Spinazzi, M., Stankova, P., Starr, J., Stary, C., Stelfa, G., Stepto, NK., Stiban, J., Stier, A., Stocker, R., Storder, J., Sumbalova, Z., Suomalainen, A., Suravajhala, P., Svalbe, B., Swerdlow, RH., Swiniuch, D., Szabo, I., Szewczyk, A., Szibor, M., Tanaka, M., Tandler, B., Tarnopolsky, MA., Tausan, D., Tavernarakis, N., Tepp, K., Thakkar, H., Thapa, M., Thyfault, JP., Tomar, D., Ton, R., Torp, MK., Towheed, A., Tretter, L., Trewin, AJ., Trifunovic, A., Trivigno, C., Tronstad, KJ., Trougakos, IP., Truu, L., Tuncay, E., Turan, B., Tyrrell, DJ., Urban, T., Valentine, JM., Van Bergen, NJ., Van Hove, J., Varricchio, F., Vella, J., Vendelin, M., Vercesi, AE., Victor, VM., Vieira Ligo Teixeira, C., Vidimce, J., Viel, C., Vieyra, A., Vilks, K., Villena, JA., Vincent, V., Vinogradov, AD., Viscomi, C., Vitorino, RMP., Vogt, S., Volani, C., Volska, K., Votion, DM., Vujacic-Mirski, K., Wagner, BA., Ward, ML., Warnsmann, V., Wasserman, DH., Watala, C., Wei, YH., Whitfield, J., Wickert, A., Wieckowski, MR., Wiesner, RJ., Williams, CM., Winwood-Smith, H., Wohlgemuth, SE., Wohlwend, M., Wolff, JN., Wrutniak-Cabello, C., Wuest, RCI., Yokota, T., Zablocki, K., Zanon, A., Zanou, N., Zaugg, K., Zaugg, M., Zdrazilova, L., Zhang, Y., Zhang, YZ., Zikova, A., Zischka, H., Zorzano, A., and Zvejniece, L.

Subjects
Mitochondrial respiratory control, coupling control, mitochondrial preparations, protonmotive force, uncoupling, oxidative phosphorylation, OXPHOS, efficiency, electron transfer, ET, proton leak, LEAK, residual oxygen consumption, ROX, State 2, State 3, State 4, normalization, flow, flux, O2
Abstract

As the knowledge base and importance of mitochondrial physiology to human health expands, the necessity for harmonizing the terminologyconcerning mitochondrial respiratory states and rates has become increasingly apparent. Thechemiosmotic theoryestablishes the mechanism of energy transformationandcoupling in oxidative phosphorylation. Theunifying concept of the protonmotive force providestheframeworkfordeveloping a consistent theoretical foundation ofmitochondrial physiology and bioenergetics.We followguidelines of the International Union of Pure and Applied Chemistry(IUPAC)onterminology inphysical chemistry, extended by considerationsofopen systems and thermodynamicsof irreversible processes.Theconcept-driven constructive terminology incorporates the meaning of each quantity and alignsconcepts and symbols withthe nomenclature of classicalbioenergetics. We endeavour to provide a balanced view ofmitochondrial respiratory control and a critical discussion on reporting data of mitochondrial respiration in terms of metabolic flows and fluxes.Uniform standards for evaluation of respiratory states and rates will ultimatelycontribute to reproducibility between laboratories and thussupport the development of databases of mitochondrial respiratory function in species, tissues, and cells.Clarity of concept and consistency of nomenclature facilitate effective transdisciplinary communication, education, and ultimately further discovery.

Published
2019

3. Decreases in Circulating Concentrations of Long-Chain Acylcarnitines and Free Fatty Acids During the Glucose Tolerance Test Represent Tissue-Specific Insulin Sensitivity.

Author

Makarova E, Makrecka-Kuka M, Vilks K, Volska K, Sevostjanovs E, Grinberga S, Zarkova-Malkova O, Dambrova M, and Liepinsh E

Abstract

Background: Insulin plays a pivotal role in the regulation of both carbohydrate and lipid intermediate turnover and metabolism. In the transition from a fasted to fed state, insulin action inhibits lipolysis in adipocytes, and acylcarnitine synthesis in the muscles and heart. The aim of this study was to measure free fatty acid (FFA) and acylcarnitine levels during the glucose tolerance test as indicators of tissue-specific insulin resistance. Results: Insulin release in response to glucose administration decreased both FFA and long-chain acylcarnitine levels in plasma in healthy control animals by 30% (120 min). The glucose tolerance test and [ 3 H]-deoxy-D-glucose uptake in tissues revealed that high fat diet-induced lipid overload in C57bl/6N mice evoked only adipose tissue insulin resistance, and plasma levels of FFAs did not decrease after glucose administration. In comparison, db/db mice developed type 2 diabetes with severely impaired insulin sensitivity and up to 70% lower glucose uptake in both adipose tissues and muscles (skeletal muscle and heart), and both plasma concentrations of FFAs and long-chain acylcarnitines did not decrease in response to glucose administration. Conclusions: These results link impaired adipose tissue insulin sensitivity with continuous FFA release in the transition from a fasted to postprandial state, while a blunted decrease in long-chain acylcarnitine levels is associated with muscle and heart insulin resistance., (Copyright © 2019 Makarova, Makrecka-Kuka, Vilks, Volska, Sevostjanovs, Grinberga, Zarkova-Malkova, Dambrova and Liepinsh.)

Published
2019
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4. Plasma acylcarnitine concentrations reflect the acylcarnitine profile in cardiac tissues.

Author

Makrecka-Kuka M, Sevostjanovs E, Vilks K, Volska K, Antone U, Kuka J, Makarova E, Pugovics O, Dambrova M, and Liepinsh E

Subjects
Animals, Blood Glucose, Carnitine metabolism, Glucose Tolerance Test, Insulin blood, Liver metabolism, Male, Metabolic Diseases metabolism, Mice, Muscle, Skeletal metabolism, Random Allocation, Rats, Wistar, Running physiology, Carnitine analogs & derivatives, Myocardium metabolism
Abstract

Increased plasma concentrations of acylcarnitines (ACs) are suggested as a marker of metabolism disorders. The aim of the present study was to clarify which tissues are responsible for changes in the AC pool in plasma. The concentrations of medium- and long-chain ACs were changing during the fed-fast cycle in rat heart, muscles and liver. After 60 min running exercise, AC content was increased in fasted mice muscles, but not in plasma or heart. After glucose bolus administration in fasted rats, the AC concentrations in plasma decreased after 30 min but then began to increase, while in the muscles and liver, the contents of medium- and long-chain ACs were unchanged or even increased. Only the heart showed a decrease in medium- and long-chain AC contents that was similar to that observed in plasma. In isolated rat heart, but not isolated-contracting mice muscles, the significant efflux of medium- and long-chain ACs was observed. The efflux was reduced by 40% after the addition of glucose and insulin to the perfusion solution. Overall, these results indicate that during fed-fast cycle shifting the heart determines the medium- and long-chain AC profile in plasma, due to a rapid response to the availability of circulating energy substrates.

Published
2017
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5. Acute and long-term administration of palmitoylcarnitine induces muscle-specific insulin resistance in mice.

Author

Liepinsh E, Makrecka-Kuka M, Makarova E, Volska K, Vilks K, Sevostjanovs E, Antone U, Kuka J, Vilskersts R, Lola D, Loza E, Grinberga S, and Dambrova M

Subjects
Animals, Blood Glucose drug effects, Carbohydrate Metabolism drug effects, Carnitine analogs & derivatives, Carnitine metabolism, Dietary Fats, Glucose metabolism, Humans, Insulin metabolism, Lipid Metabolism drug effects, Mice, Muscle, Skeletal pathology, Energy Metabolism drug effects, Insulin Resistance genetics, Muscle, Skeletal metabolism, Palmitoylcarnitine administration & dosage
Abstract

Acylcarnitine accumulation has been linked to perturbations in energy metabolism pathways. In this study, we demonstrate that long-chain (LC) acylcarnitines are active metabolites involved in the regulation of glucose metabolism in vivo. Single-dose administration of palmitoylcarnitine (PC) in fed mice induced marked insulin insensitivity, decreased glucose uptake in muscles, and elevated blood glucose levels. Increase in the content of LC acylcarnitine induced insulin resistance by impairing Akt phosphorylation at Ser473. The long-term administration of PC using slow-release osmotic minipumps induced marked hyperinsulinemia, insulin resistance, and glucose intolerance, suggesting that the permanent accumulation of LC acylcarnitines can accelerate the progression of insulin resistance. The decrease of acylcarnitine content significantly improved glucose tolerance in a mouse model of diet-induced glucose intolerance. In conclusion, we show that the physiological increase in content of acylcarnitines ensures the transition from a fed to fasted state in order to limit glucose metabolism in the fasted state. In the fed state, the inability of insulin to inhibit LC acylcarnitine production induces disturbances in glucose uptake and metabolism. The reduction of acylcarnitine content could be an effective strategy to improve insulin sensitivity. © 2017 BioFactors, 43(5):718-730, 2017., (© 2017 The Authors BioFactors published by Wiley Periodicals, Inc. on behalf of International Union of Biochemistry and Molecular Biology.)

Published
2017
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6. Trimethylamine N-oxide impairs pyruvate and fatty acid oxidation in cardiac mitochondria.

Author

Makrecka-Kuka M, Volska K, Antone U, Vilskersts R, Grinberga S, Bandere D, Liepinsh E, and Dambrova M

Subjects
Animals, Dose-Response Relationship, Drug, Male, Mice, Inbred ICR, Mitochondria, Heart metabolism, Oxidation-Reduction, Reactive Oxygen Species metabolism, Energy Metabolism drug effects, Fatty Acids metabolism, Methylamines toxicity, Mitochondria, Heart drug effects, Myocardium metabolism, Pyruvic Acid metabolism
Abstract

Increased plasma concentration of trimethylamine N-oxide (TMAO), a proatherogenic metabolite, has been linked to adverse cardiovascular outcomes; however, it remains unclear whether TMAO is a biomarker or whether it induces direct detrimental cardiovascular effects. Because altered cardiac energy metabolism and mitochondrial dysfunction play crucial roles in the development of cardiovascular diseases, we hypothesized that increased TMAO concentration may alter mitochondrial energy metabolism. The aim of the present study was to determine the effects of TMAO on cardiac mitochondrial energy metabolism. Acute exposure of cardiac fibers to TMAO decreased LEAK (substrate-dependent) and OXPHOS (oxidative phosphorylation-dependent) mitochondrial respiration with pyruvate and impaired substrate flux via pyruvate dehydrogenase. The administration of TMAO at a dose of 120mg/kg for 8 weeks increased TMAO concentration in plasma and cardiac tissues 22-23 times to about 15μM and 11nmol/g, respectively. Long-term TMAO administration decreased mitochondrial LEAK state respiration with pyruvate by 30% without affecting OXPHOS state respiration. However, no significant changes in mitochondrial reactive oxygen species production were observed after acute exposure of cardiac fibers to TMAO under physiological conditions. In addition, both long-term TMAO administration and acute exposure to TMAO decreased respiration with palmitoyl-CoA indicating impaired β-oxidation. Taken together, our results demonstrate that increased TMAO concentration impairs pyruvate and fatty acid oxidation in cardiac mitochondria. Thus, the accumulation of TMAO in cardiac tissues leads to disturbances in energy metabolism that can increase the severity of cardiovascular events., (Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.)

Published
2017
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7. Decreased acylcarnitine content improves insulin sensitivity in experimental mice models of insulin resistance.

Author

Liepinsh E, Makrecka-Kuka M, Makarova E, Volska K, Svalbe B, Sevostjanovs E, Grinberga S, Kuka J, and Dambrova M

Subjects
Animals, Blood Glucose drug effects, Carnitine blood, Carnitine metabolism, Diabetes Mellitus blood, Diabetes Mellitus drug therapy, Diabetes Mellitus metabolism, Diabetes Mellitus, Experimental blood, Diabetes Mellitus, Experimental drug therapy, Diabetes Mellitus, Experimental metabolism, Diet, High-Fat adverse effects, Disease Models, Animal, Fatty Acids metabolism, Gene Expression drug effects, Glucose metabolism, Lipid Metabolism drug effects, Male, Mice, Mice, Inbred C57BL, Muscles drug effects, Muscles metabolism, PPAR alpha metabolism, Quaternary Ammonium Compounds pharmacology, Signal Transduction drug effects, gamma-Aminobutyric Acid analogs & derivatives, gamma-Aminobutyric Acid pharmacology, Carnitine analogs & derivatives, Insulin metabolism, Insulin Resistance physiology, Physical Conditioning, Animal physiology
Abstract

The important pathological consequences of insulin resistance arise from the detrimental effects of accumulated long-chain fatty acids and their respective acylcarnitines. The aim of this study was to test whether exercise combined with decreasing the content of long-chain acylcarnitines represents an effective strategy to improve insulin sensitivity in diabetes. We used a novel compound, 4-[ethyl(dimethyl)ammonio]butanoate (methyl-GBB), treatment and exercise to decrease acylcarnitine contents in the plasma and muscles in the insulin resistance models of high fat diet (HFD) fed C57BL/6 mice and db/db mice. The methyl-GBB treatment induced a substantial decrease in all acylcarnitine concentrations in both fed and fasted states as well as when it was combined with exercise. In the HFD fed mice methyl-GBB treatment improved both glucose and insulin tolerance. Methyl-GBB administration, exercise and the combination of both improved insulin sensitivity and reduced blood glucose levels in db/db mice. Methyl-GBB administration and the combination of the drug and exercise activated the PPARα/PGC1α signaling pathway and stimulated the corresponding target gene expression. Insulin insensitivity in db/db mice was not induced by significantly increased fatty acid metabolism, while increased insulin sensitivity by both treatments was not related to decreased fatty acid metabolism in muscles. The pharmacologically reduced long-chain acylcarnitine content represents an effective strategy to improve insulin sensitivity. The methyl-GBB treatment and lifestyle changes via increased physical activity for one hour a day have additive insulin sensitizing effects in db/db mice., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

Published
2016
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8. The neuroprotective effects of R-phenibut after focal cerebral ischemia.

Author

Vavers E, Zvejniece L, Svalbe B, Volska K, Makarova E, Liepinsh E, Rizhanova K, Liepins V, and Dambrova M

Subjects
Animals, Brain Ischemia metabolism, Brain-Derived Neurotrophic Factor metabolism, Calcium Channels metabolism, Disease Models, Animal, Forelimb drug effects, Forelimb metabolism, Infarction, Middle Cerebral Artery drug therapy, Infarction, Middle Cerebral Artery metabolism, Male, Rats, Rats, Wistar, Receptors, GABA-B metabolism, Sensorimotor Cortex metabolism, Stroke drug therapy, Stroke metabolism, Vascular Endothelial Growth Factor A metabolism, Brain Ischemia drug therapy, Eye Proteins pharmacology, Neuroprotective Agents pharmacology, Sensorimotor Cortex drug effects
Abstract

R-phenibut is a γ-aminobutyric acid (GABA)-B receptor and α 2 -δ subunit of the voltage-dependent calcium channel (VDCC) ligand. The aim of the present study was to test the effects of R-phenibut on the motor, sensory and tactile functions and histological outcomes in rats following transient middle cerebral artery occlusion (MCAO). In this study, MCAO was induced by filament insertion (f-MCAO) or endothelin-1 (ET1) microinjection (ET1-MCAO) in male Wistar or CD rats, respectively. R-phenibut was administrated at doses of 10 and 50mg/kg for 14 days in the f-MCAO or 7 days in the ET1-MCAO. The vibrissae-evoked forelimb-placing and limb-placing tests were used to assess sensorimotor, tactile and proprioceptive function. Quantitative reverse transcriptase-PCR was used to detect brain-derived neurotrophic factor (BDNF) and vascular endothelial growth factor (VEGF) gene expression in the damaged brain hemisphere. Both f-MCAO and ET1-MCAO resulted in statistically significant impairment of sensorimotor function and brain infarction. R-phenibut at a dose of 10mg/kg significantly improved histological outcome at day 7 in the ET1-MCAO. R-phenibut treatment at a dose of 50mg/kg significantly alleviated reduction of brain volume in damaged hemisphere in both f-MCAO and ET1-MCAO. In R-phenibut treated animals a trend of recovery of tactile and proprioceptive stimulation in the vibrissae-evoked forelimb-placing test was observed. After R-phenibut treatment at a dose of 50mg/kg statistically significant increase of BDNF and VEGF gene expression was found in damaged brain hemisphere. Taken together, obtained results provide evidence for the neuroprotective activity of R-phenibut in experimental models of stroke. These effects might be related to the modulatory effects of the drug on the GABA-B receptor and α 2 -δ subunit of VDCC., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

Published
2016
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9. Long-chain acylcarnitines determine ischaemia/reperfusion-induced damage in heart mitochondria.

Author

Liepinsh E, Makrecka-Kuka M, Volska K, Kuka J, Makarova E, Antone U, Sevostjanovs E, Vilskersts R, Strods A, Tars K, and Dambrova M

Subjects
Animals, Carnitine metabolism, Carnitine O-Palmitoyltransferase metabolism, Male, Myocardial Reperfusion Injury pathology, Oxidative Phosphorylation, Rats, Rats, Wistar, Carnitine analogs & derivatives, Mitochondria, Heart metabolism, Myocardial Reperfusion Injury metabolism
Abstract

The accumulation of long-chain fatty acids (FAs) and their CoA and carnitine esters is observed in the ischaemic myocardium after acute ischaemia/reperfusion. The aim of the present study was to identify harmful FA intermediates and their detrimental mechanisms of action in mitochondria and the ischaemic myocardium. In the present study, we found that the long-chain acyl-CoA and acylcarnitine content is increased in mitochondria isolated from an ischaemic area of the myocardium. In analysing the FA derivative content, we discovered that long-chain acylcarnitines, but not acyl-CoAs, accumulate at concentrations that are harmful to mitochondria. Acylcarnitine accumulation in the mitochondrial intermembrane space is a result of increased carnitine palmitoyltransferase 1 (CPT1) and decreased carnitine palmitoyltransferase 2 (CPT2) activity in ischaemic myocardium and it leads to inhibition of oxidative phosphorylation, which in turn induces mitochondrial membrane hyperpolarization and stimulates the production of reactive oxygen species (ROS) in cardiac mitochondria. Thanks to protection mediated by acyl-CoA-binding protein (ACBP), the heart is much better guarded against the damaging effects of acyl-CoAs than against acylcarnitines. Supplementation of perfusion buffer with palmitoylcarnitine (PC) before occlusion resulted in a 2-fold increase in the acylcarnitine content of the heart and increased the infarct size (IS) by 33%. A pharmacologically induced decrease in the mitochondrial acylcarnitine content reduced the IS by 44%. Long-chain acylcarnitines are harmful FA intermediates, accumulating in ischaemic heart mitochondria and inducing inhibition of oxidative phosphorylation. Therefore, decreasing the acylcarnitine content via cardioprotective drugs may represent a novel treatment strategy., (© 2016 The Author(s). published by Portland Press Limited on behalf of the Biochemical Society.)

Published
2016
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10. Methyl-γ-butyrobetaine decreases levels of acylcarnitines and attenuates the development of atherosclerosis.

Author

Vilskersts R, Kuka J, Liepinsh E, Makrecka-Kuka M, Volska K, Makarova E, Sevostjanovs E, Cirule H, Grinberga S, and Dambrova M

Subjects
Animals, Aorta drug effects, Aorta metabolism, Apolipoproteins E metabolism, Betaine pharmacology, Carnitine metabolism, Carnitine pharmacology, Disease Progression, Female, Male, Mice, Atherosclerosis drug therapy, Atherosclerosis metabolism, Betaine analogs & derivatives, Carnitine analogs & derivatives
Abstract

Objective: The elevation of the levels of l-carnitine and its fatty acid esters, acylcarnitines, in tissue or plasma has been linked to the development of atherosclerosis. Recently, a potent inhibitor of l-carnitine biosynthesis and transport, methyl-γ-butyrobetaine (methyl-GBB), was discovered. In this study, we evaluated the effects of γ-butyrobetaine (GBB), l-carnitine and methyl-GBB administration on the progression of atherosclerosis., Methods: Apolipoprotein E knockout (apoE(-/-)) mice were treated with methyl-GBB, l-carnitine or GBB for 4months. Following the treatment, the amount of atherosclerotic lesions, the number of immune cells in atherosclerotic lesions and the plasma lipid profile were analysed. The l-carnitine and acylcarnitine levels were determined in the aortic tissues of CD-1 outbred mice 2weeks after treatment with methyl-GBB at the dose of 10mg/kg., Results: Treatment with methyl-GBB decreased the acylcarnitine and l-carnitine levels in the aortic tissues by seventeen- and ten-fold, respectively. Methyl-GBB treatment at a dose of 10mg/kg reduced the size of atherosclerotic plaques by 36%. Neither l-carnitine nor GBB treatment affected the development of atherosclerosis., Conclusions: Methyl-GBB administration significantly attenuated the development of atherosclerosis in apoE(-/-)mice. Our results demonstrate that decreasing the acylcarnitine pools can attenuate the development of atherosclerosis., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Published
2015
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11. Long-chain acylcarnitine content determines the pattern of energy metabolism in cardiac mitochondria.

Author

Makrecka M, Kuka J, Volska K, Antone U, Sevostjanovs E, Cirule H, Grinberga S, Pugovics O, Dambrova M, and Liepinsh E

Subjects
Animals, Carnitine metabolism, Fasting, Fatty Acids metabolism, Male, Mice, Mice, Inbred ICR, Models, Animal, Rats, Rats, Wistar, Carnitine analogs & derivatives, Energy Metabolism, Glucose metabolism, Mitochondria, Heart physiology, Palmitoylcarnitine administration & dosage
Abstract

In the heart, a nutritional state (fed or fasted) is characterized by a unique energy metabolism pattern determined by the availability of substrates. Increased availability of acylcarnitines has been associated with decreased glucose utilization; however, the effects of long-chain acylcarnitines on glucose metabolism have not been previously studied. We tested how changes in long-chain acylcarnitine content regulate the metabolism of glucose and long-chain fatty acids in cardiac mitochondria in fed and fasted states. We examined the concentrations of metabolic intermediates in plasma and cardiac tissues under fed and fasted states. The effects of substrate availability and their competition for energy production at the mitochondrial level were studied in isolated rat cardiac mitochondria. The availability of long-chain acylcarnitines in plasma reflected their content in cardiac tissue in the fed and fasted states, and acylcarnitine content in the heart was fivefold higher in fasted state compared to the fed state. In substrate competition experiments, pyruvate and fatty acid metabolites effectively competed for the energy production pathway; however, only the physiological content of acylcarnitine significantly reduced pyruvate and lactate oxidation in mitochondria. The increased availability of long-chain acylcarnitine significantly reduced glucose utilization in isolated rat heart model and in vivo. Our results demonstrate that changes in long-chain acylcarnitine contents could orchestrate the interplay between the metabolism of pyruvate-lactate and long-chain fatty acids, and thus determine the pattern of energy metabolism in cardiac mitochondria.

Published
2014
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12. Mildronate, the inhibitor of L-carnitine transport, induces brain mitochondrial uncoupling and protects against anoxia-reoxygenation.

Author

Makrecka M, Svalbe B, Volska K, Sevostjanovs E, Liepins J, Grinberga S, Pugovics O, Liepinsh E, and Dambrova M

Subjects
Acyl Coenzyme A metabolism, Adenosine Triphosphate metabolism, Animals, Brain metabolism, Carnitine metabolism, Carnitine Acyltransferases metabolism, Cell Respiration drug effects, Hypoxia metabolism, Male, Mitochondria metabolism, Oxygen metabolism, Rats, Rats, Wistar, Brain drug effects, Carnitine antagonists & inhibitors, Methylhydrazines pharmacology, Mitochondria drug effects, Neuroprotective Agents pharmacology
Abstract

The preservation of mitochondrial function is essential for normal brain function after ischaemia-reperfusion injury. l-carnitine is a cofactor involved in the regulation of cellular energy metabolism. Recently, it has been shown that mildronate, an inhibitor of l-carnitine transport, improves neurological outcome after ischaemic damage of brain tissues. The aim of the present study was to elucidate the mitochondria targeted neuroprotective action of mildronate in the model of anoxia-reoxygenation-induced injury. Wistar rats were treated daily with mildronate (per os; 100mg/kg) for 14 days. The acyl-carnitine profile was determined in the brain tissues. Mitochondrial respiration and the activities of carnitine acetyltransferase (CrAT) and tricarboxylic acid (TCA) cycle enzymes were measured. To assess tolerance to ischaemia, isolated mitochondria were subjected to anoxia followed by reoxygenation. The mildronate treatment significantly reduced the concentrations of free l-carnitine (FC) and short-chain acyl-carnitine (AC) in brain tissue by 40-76%, without affecting the AC:FC ratio. The activities of CrAT and TCA cycle enzymes were slightly increased after mildronate treatment. Despite partially induced uncoupling, mildronate treatment did not affect mitochondrial bioenergetics function under normoxic conditions. After exposure to anoxia-reoxygenation, state 3 respiration and the respiration control ratio were higher in the mildronate-treated group. The results obtained demonstrate that mildronate treatment improves tolerance against anoxia-reoxygenation due to an uncoupling preconditioning-like effect. Regulating l-carnitine availability provides a potential novel target for the treatment of cerebral ischaemia and related complications., (Copyright © 2013 Elsevier B.V. All rights reserved.)

Published
2014
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