Publications (11)22.9 Total impact
-
Article: Taurine Deficiency and MELAS Are Closely Related Syndromes.
[show abstract] [hide abstract]
ABSTRACT: MELAS (mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes) is a mitochondrial disease caused by one or more mutations of tRNA(Leu(UUR)). These mutations reduce both the aminoacylation of tRNA(Leu(UUR)) and a posttranslational modification in the wobble position of tRNA(Leu(UUR)). Both changes result in reduced transcription of mitochondria-encoded proteins; however, reduced aminoacylation affects the decoding of both UUG and UUA while the wobble defect specifically diminishes UUG decoding. Because 12 out of the 13 mitochondria-encoded proteins are more dependent on UUA decoding than UUG decoding, the aminoacylation defect should have a more profound effect on protein synthesis than the wobble defect, which more specifically alters the expression of one mitochondria-encoded protein, ND6. Taurine serves as a substrate in the formation of 5-taurinomethyluridine-tRNA(Leu(UUR)); therefore, taurine deficiency should mimic 5-taurinomethyluridine-tRNA(Leu(UUR)) deficiency. Hence, the wobble hypothesis predicts that the symptoms of MELAS mimic those of taurine deficiency, provided that the dominant defect in MELAS is wobble modification deficiency. On the other hand, if the aminoacylation defect dominates, significant differences should exist between taurine deficiency and MELAS. The present review tests this hypothesis by comparing the symptoms of MELAS and taurine deficiency.Advances in experimental medicine and biology 01/2013; 776:153-65. · 1.09 Impact Factor -
Article: Role of taurine in the pathologies of MELAS and MERRF.
[show abstract] [hide abstract]
ABSTRACT: Taurine is an abundant β-amino acid that concentrates in the mitochondria, where it participates in the conjugation of tRNAs for leucine, lysine, glutamate and glutamine. The formation of 5-taurinomethyluridine-tRNA strengthens the interaction of the anticodon with the codon, thereby promoting the decoding of several codons, including those for AAG, UUG, CAG and GAG. By preventing these series of events, taurine deficiency appears to diminish the formation of 5-taurinomethyluridine and causes inefficient decoding for the mitochondrial codons of leucine, lysine, glutamate and glutamine. The resulting reduction in the biosynthesis of mitochondria-encoded proteins deprives the respiratory chain of subunits required for the assembly of respiratory chain complexes. Hence, taurine deficiency is associated with a reduction in oxygen consumption, an elevation in glycolysis and lactate production and a decline in ATP production. A similar sequence of events takes place in mitochondrial diseases MELAS (mitochondrial myopathy, encephalopathy, lactic acidosis and stroke-like episodes) and MERRF (myoclonic epilepsy and ragged-red fiber syndrome). In both diseases, mutations in their respective tRNAs interfere with the formation of 5-taurinomethyluridine in the wobble position. Hence, the taurine-deficient phenotype resembles the phenotypes of MELAS and MERRF.Amino Acids 11/2012; · 3.25 Impact Factor -
Article: Effect of taurine on ischemia-reperfusion injury.
[show abstract] [hide abstract]
ABSTRACT: Taurine is an abundant β-amino acid that regulates several events that dramatically influence the development of ischemia-reperfusion injury. One of these events is the extrusion of taurine and Na(+) from the cell via the taurine/Na(+) symport. The loss of Na(+) during the ischemia-reperfusion insult limits the amount of available Na(+) for Na(+)/Ca(2+) exchange, an important process in the development of Ca(2+) overload and the activation of the mitochondrial permeability transition, a key process in ischemia-reperfusion mediated cell death. Taurine also prevents excessive generation of reactive oxygen species by the respiratory chain, an event that also limits the activation of the MPT. Because taurine is an osmoregulator, changes in taurine concentration trigger "osmotic preconditioning," a process that activates an Akt-dependent cytoprotective signaling pathway that inhibits MPT pore formation. These effects of taurine have clinical implications, as experimental evidence reveals potential promise of taurine therapy in preventing cardiac damage during bypass surgery, heart transplantation and myocardial infarction. Moreover, severe loss of taurine from the heart during an ischemia-reperfusion insult may increase the risk of ventricular remodeling and development of heart failure.Amino Acids 08/2012; · 3.25 Impact Factor -
Article: Role of oxidative stress in diabetes-mediated vascular dysfunction: Unifying hypothesis of diabetes revisited.
[show abstract] [hide abstract]
ABSTRACT: Oxidative stress is recognized as a key participant in the development of diabetic complications in the vasculature. One of the seminal studies advancing the role of oxidative stress in vascular endothelial cells proposed that oxidative stress-mediated diversion of glycolytic intermediates into pathological pathways was a key underlying element in the development of diabetic complications. It is widely recognized that flux through glycolysis slows during diabetes. However, several bottlenecks develop in the glycolytic pathway, including glucose transport, phosphofructokinase, glyceraldehyde-3-phosphate dehydrogenase and pyruvate kinase. Of these limiting steps in glycolysis, glyceraldehyde-3-phosphate dehydrogenase is most sensitive to oxidative stress, leading to the hypothesis that glyceraldehyde-3-phosphate inactivation by ribosylation underlies the diversion of glycolytic intermediates into pathological pathways. However, recent studies question the mechanism underlying the effect of reactive oxygen species on key enzymes of the glycolytic pathway. The present review critiques the major premises of the hypothesis and concludes that further study of the role of oxidative stress in the development of diabetes-mediated vasculature dysfunction is warranted.Vascular Pharmacology 03/2012; 57(5-6):139-49. · 1.99 Impact Factor -
Article: Mechanism underlying the antioxidant activity of taurine: prevention of mitochondrial oxidant production.
[show abstract] [hide abstract]
ABSTRACT: An important function of the β-amino acid, taurine, is the regulation of oxidative stress. However, taurine is neither a classical scavenger nor a regulator of the antioxidative defenses, leaving uncertain the mechanism underlying the antioxidant activity of taurine. In the present study, the taurine antagonist and taurine transport inhibitor, β-alanine, was used to examine the mechanism underlying the antioxidant activity of taurine. Exposure of isolated cardiomyocytes to medium containing β-alanine for a period of 48 h led to a 45% decrease in taurine content and an increase in mitochondrial oxidative stress, as evidenced by enhanced superoxide generation, the inactivation of the oxidant sensitive enzyme, aconitase, and the oxidation of glutathione. Associated with the increase in oxidative stress was a decline in electron transport activity, with the activities of respiratory chain complexes I and III declining 50-65% and oxygen consumption falling 30%. A reduction in respiratory chain activity coupled with an increase in oxidative stress is commonly caused by the development of a bottleneck in electron transport that leads to the diversion of electrons from the respiratory chain to the acceptor oxygen forming in the process superoxide. Because β-alanine exposure significantly reduces the levels of respiratory chain complex subunits, ND5 and ND6, the bottleneck in electron transport appears to be caused by impaired synthesis of key subunits of the electron transport chain complexes. Co-administration of taurine with β-alanine largely prevents the mitochondrial effects of β-alanine, but treatment of the cells with 5 mM taurine in the absence of β-alanine has no effect on the mitochondria, likely because taurine treatment has little effect on cellular taurine levels. Thus, taurine serves as a regulator of mitochondrial protein synthesis, thereby enhancing electron transport chain activity and protecting the mitochondria against excessive superoxide generation.Amino Acids 06/2011; 42(6):2223-32. · 3.25 Impact Factor -
Article: Role of mitochondrial permeability transition in taurine deficiency-induced apoptosis.
[show abstract] [hide abstract]
ABSTRACT: It has recently been shown that taurine deficiency leads to impaired respiratory chain function, resulting in reduced ATP generation and enhanced oxidative stress. Because cardiomyopathy develops in taurine-deficient animals, the hypothesis that mitochondrial oxidative stress may contribute to the development of cardiomyocyte dysfunction and cell death was tested. Isolated neonatal cardiomyocytes incubated in medium containing the taurine transport inhibitor, beta-alanine, lost nearly one-half of their cellular taurine content after 48 h. Accompanying the loss of taurine was a time-dependent increase in apoptosis, which was prevented by the mitochondrial permeability transition inhibitor, cyclosporin A. Two taurine-dependent factors, oxidative stress and calcium overload, serve as important regulators of the mitochondrial permeability transition. Although taurine deficiency slowed the removal of calcium from the cytosol, it had no effect on diastolic calcium content and only modestly reduced systolic calcium content, suggesting that calcium overload is not the trigger for mitochondrial permeability transition pore formation. On the other hand, the glutathione redox ratio was significantly altered in the taurine-deficient cardiomyocyte, suggesting that oxidative stress is the primary initiator of mitochondrial permeability transition and apoptosis in the taurine-deficient cardiomyocyte.Experimental and clinical cardiology 01/2011; 16(4):125-8. · 0.58 Impact Factor -
Chapter: MELAS Syndrome: Mediated by Impaired Taurinomethyluridine Synthesis
[show abstract] [hide abstract]
ABSTRACT: Taurine (2-aminoethanesulfonate) is a ubiquitous β-amino acid found in a very high concentration in excitable tissue. One of its most important functions is its conjugation with uridine located in the wobble position of tRNALeu(UUR). Because the wobble modification stabilizes the UG base pairing, it facilitates the decoding of UUG codons. Consequently, taurine deficiency, which reduces the wobble modification, decreases the synthesis of proteins whose mRNA has a high UUG codon content. The synthesis of one such protein, ND6, plunges 60% after a 50% decline in taurine content. Because ND6 is a subunit of respiratory chain complex I, taurine depletion also leads to a decline in the activity of the electron transport chain. A similar sequence of events occurs in the mitochondrial disease, MELAS (mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes). The initial event in most MELAS patients is the appearance of one mutation in tRNALeu(UUR), which in turn blocks the taurinomethyl modification of the wobble nucleotide. As a result, the synthesis of ND6 and other UUG-dependent proteins falls. As respiratory function declines, the generation of ATP is compromised and in some cases the mitochondria begin to produce oxidants. Because mutations in tRNALeu(UUR) trigger multiple events, the identification of which event causes mitochondrial dysfunction has been challenging. The taurine-deficient model has aided in the identification of at least one pathological pathway that contributes to the development of the MELAS disorder. Keywordsβ-Alanine-cardiomyopathy-MELAS syndrome-mitochondria-encoded proteins-mitochondrial disease-ND6-posttranscriptional modification-respiratory chain activity-taurine-Taurinomethyluridine-tRNA aminoacylation-tRNALeu(UUR) -wobble nucleotide12/2010: pages 93-100; -
Article: Effect of hypernatremia on injury caused by energy deficiency: role of T-type Ca2+ channel.
[show abstract] [hide abstract]
ABSTRACT: Hypernatremia exerts multiple cellular effects, many of which could influence the outcome of an ischemic event. To further evaluate these effects of hypernatremia, isolated neonatal cardiomyocytes were chronically incubated with medium containing either normal (142 mM) or elevated sodium (167 mM) and then transferred to medium containing deoxyglucose and the electron transport chain inhibitor amobarbital. Chronic hypernatremia diminished the degree of calcium accumulation and reactive oxygen species generation during the period of metabolic inhibition. The improvement in calcium homeostasis was traced in part to the downregulation of the Ca(V)3.1 T-type calcium channel, as deficiency in the Ca(V)3.1 subtype using short hairpin RNA or treatment with an inhibitor of the Ca(V)3.1 variant of the T-type calcium channel (i.e., diphenylhydantoin) attenuated energy deficiency-mediated calcium accumulation and cell death. Although hyperosmotically stressed cells (exposed to 50 mM mannitol) had no effect on T-type calcium channel activity, they were also resistant to death during metabolic inhibition. Both hyperosmotic stress and hypernatremia activated Akt, suggesting that they initiate the phosphatidylinositol 3-kinase/Akt cytoprotective pathway, which protects the cell against calcium overload and oxidative stress. Thus hypernatremia appears to protect the cell against metabolic inhibition by promoting the downregulation of the T-type calcium channel and stimulating cytoprotective protein kinase pathways.AJP Cell Physiology 08/2010; 299(2):C289-97. · 3.54 Impact Factor -
Article: Effect of beta-alanine treatment on mitochondrial taurine level and 5-taurinomethyluridine content.
[show abstract] [hide abstract]
ABSTRACT: The beta-amino acid, taurine, is a nutritional requirement in some species. In these species, the depletion of intracellular stores of taurine leads to the development of severe organ dysfunction. The basis underlying these defects is poorly understood, although there is some suggestion that oxidative stress may contribute to the abnormalities. Recent studies indicate that taurine is required for normal mitochondrial protein synthesis and normal electron transport chain activity; it is known that defects in these events can lead to severe mitochondrial oxidative stress. The present study examines the effect of taurine deficiency on the first step of mitochondrial protein synthesis regulation by taurine, namely, the formation of taurinomethyluridine containing tRNA. Isolated rat cardiomyocytes were rendered taurine deficient by incubation with medium containing the taurine transport inhibitor, beta-alanine. The time course of cellular and mitochondrial taurine depletion was measured. The primer extension method was employed to evaluate the effect of beta-alanine treatment on taurinomethyluridine content of tRNALeu. The protein levels of ND6 were also determined by Western blot analysis. beta-alanine caused a time-dependent decrease in cellular taurine content, which were reduced in half after 48 hrs of incubation. The amount of taurine in the mitochondria was considerably less than that in the cytosol and was unaffected by beta-alanine treatment. Approximately 70% of the tRNALeu in the untreated cell lacked taurinomethyluridine and these levels were unchanged following beta-alanine treatment. Protein content of ND6, however, was significantly reduced after 48 hours incubation with beta-alanine. The taurine levels of the cytosol and the mitochondria are not directly coupled. The beta-alanine-mediated reduction in taurine levels is too small to affect taurinomethyluridine levels. Nonetheless, it interferes with mitochondrial protein synthesis, as exemplified by a decrease in ND6 protein content. Thus, beta-alanine does not cause alterations in mitochondrial protein synthesis through the lowering of taurine levels.Journal of Biomedical Science 01/2010; 17 Suppl 1:S25. · 2.01 Impact Factor -
Article: Physiological roles of taurine in heart and muscle.
[show abstract] [hide abstract]
ABSTRACT: Taurine (aminoethane sulfonic acid) is an ubiquitous compound, found in very high concentrations in heart and muscle. Although taurine is classified as an amino acid, it does not participate in peptide bond formation. Nonetheless, the amino group of taurine is involved in a number of important conjugation reactions as well as in the scavenging of hypochlorous acid. Because taurine is a fairly inert compound, it is an ideal modulator of basic processes, such as osmotic pressure, cation homeostasis, enzyme activity, receptor regulation, cell development and cell signalling. The present review discusses several physiological functions of taurine. First, the observation that taurine depletion leads to the development of a cardiomyopathy indicates a role for taurine in the maintenance of normal contractile function. Evidence is provided that this function of taurine is mediated by changes in the activity of key Ca2+ transporters and the modulation Ca2+ sensitivity of the myofibrils. Second, in some species, taurine is an established osmoregulator, however, in mammalian heart the osmoregulatory function of taurine has recently been questioned. Third, taurine functions as an indirect regulator of oxidative stress. Although this action of taurine has been widely discussed, its mechanism of action is unclear. A potential mechanism for the antioxidant activity of taurine is discussed. Fourth, taurine stabilizes membranes through direct interactions with phospholipids. However, its inhibition of the enzyme, phospholipid N-methyltransferase, alters the phosphatidylcholine and phosphatidylethanolamine content of membranes, which in turn affects the function of key proteins within the membrane. Finally, taurine serves as a modulator of protein kinases and phosphatases within the cardiomyocyte. The mechanism of this action has not been studied. Taurine is a chemically simple compound, but it has profound effects on cells. This has led to the suggestion that taurine is an essential or semi-essential nutrient for many mammals.Journal of Biomedical Science 01/2010; 17 Suppl 1:S2. · 2.01 Impact Factor -
Article: Proapoptotic and antiapoptotic effects of hyperglycemia: role of insulin signaling.
[show abstract] [hide abstract]
ABSTRACT: Glucose toxicity is an important initiator of cardiovascular disease, contributing to the development of insulin resistance, impaired contractile function, abnormal energy metabolism, cardiomyocyte and endothelial cell death, coronary heart disease, and heart failure. High blood glucose can, however, paradoxically protect the heart against a variety of insults, including ischemia, hypoxia, and calcium overload. To provide information on the underlying basis of these divergent actions of high glucose, the present study examined the hypothesis that the adverse effects of high glucose are linked to impaired insulin signaling, leading to a reduction in the levels of cytoprotective factors, and that the beneficial effects of high glucose occur in the absence of insulin and result in an improvement in Akt signaling. This hypothesis was evaluated by using an in vitro cardiomyocyte model that is amenable to manipulations in glucose and insulin. Prolonged exposure of the isolated neonatal cardiomyocyte to medium containing insulin and high glucose led to increased susceptibility to angiotensin II-mediated apoptosis, an effect associated with reduced levels of phospho-Akt and an increased Bax/Bcl-2 ratio. By contrast, exposure to high glucose levels in the absence of insulin rendered the cardiomyocyte resistant to angiotensin II-mediated apoptosis. Because the beneficial effects of high glucose were associated with elevations in phospho-Akt and Bcl-2 content, the cardioprotective activity of high glucose resembles the actions of insulin. Hence, the activation state of Akt is largely determined by the activity of insulin and other growth factors. Because high glucose diminishes insulin signaling, it reduces phospho-Akt levels and renders the cell susceptible to damaging insults. In the absence of insulin, however, the natural activity of high glucose is unmasked. As a result, Akt signaling is increased and the cell is rendered resistant to cell death.Canadian Journal of Physiology and Pharmacology 05/2008; 86(4):166-72. · 1.95 Impact Factor
Top co-authors
Top Journals
Institutions
-
2008–2013
-
University of South Alabama
- Department of Pharmacology
Mobile, AL, USA
-
