Taurine is a β-amino acid found in high concentrations in excitable tissues, including the heart. A significant reduction in myocardial taurine content leads to the development of a unique dilated, atrophic cardiomyopathy. One of the major functions of taurine in the heart is the regulation of the respiratory chain. Hence, we tested the hypothesis that taurine deficiency-mediated defects in respiratory chain function lead to impaired energy metabolism and reduced ATP generation. We found that while the rate of glycolysis was significantly enhanced in the taurine-deficient heart, glucose oxidation was diminished. The major site of reduced glucose oxidation was pyruvate dehydrogenase, an enzyme whose activity is reduced by the increase in the NADH/NAD+ ratio and by decreased availability of pyruvate for oxidation to acetyl CoA and changes in [Mg2+]i. Also diminished in the taurine-deficient heart was the oxidation of two other precursors of acetyl CoA, endogenous fatty acids and exogenous acetate. In the taurine-deficient heart, impaired citric acid cycle activity decreased both acetate oxidation and endogenous fatty acid oxidation, but reductions in the activity of the mitochondrial transporter, carnitine palmitoyl transferase, appeared to also contribute to the reduction in fatty acid oxidation. These changes diminished the rate of ATP production, causing a decline in the phosphocreatine/ATP ratio, a sign of reduced energy status. The findings support the hypothesis that the taurine-deficient heart is energy starved primarily because of impaired respiratory chain function, an increase in the NADH/NAD+ ratio and diminished long chain fatty acid uptake by the mitochondria. The results suggest that improved energy metabolism contributes to the beneficial effect of taurine therapy in patients suffering from heart failure.

Hyper-beta-alaninemia is a rare metabolic condition that results in elevated plasma and urinary β-alanine levels and is characterized by neurotoxicity, hypotonia, and respiratory distress. It has been proposed that at least some of the symptoms are caused by oxidative stress; however, only limited information is available on the mechanism of reactive oxygen species generation. The present study examines the hypothesis that β-alanine reduces cellular levels of taurine, which are required for normal respiratory chain function; cellular taurine depletion is known to reduce respiratory function and elevate mitochondrial superoxide generation. To test the taurine hypothesis, isolated neonatal rat cardiomyocytes and mouse embryonic fibroblasts were incubated with medium lacking or containing β-alanine. β-alanine treatment led to mitochondrial superoxide accumulation in conjunction with a decrease in oxygen consumption. The defect in β-alanine-mediated respiratory function was detected in permeabilized cells exposed to glutamate/malate but not in cells utilizing succinate, suggesting that β-alanine leads to impaired complex I activity. Taurine treatment limited mitochondrial superoxide generation, supporting a role for taurine in maintaining complex I activity. Also affected by taurine is mitochondrial morphology, as β-alanine-treated fibroblasts undergo fragmentation, a sign of unhealthy mitochondria that is reversed by taurine treatment. If left unaltered, β-alanine-treated fibroblasts also undergo mitochondrial apoptosis, as evidenced by activation of caspases 3 and 9 and the initiation of the mitochondrial permeability transition. Together, these data show that β-alanine mediates changes that reduce ATP generation and enhance oxidative stress, factors that contribute to heart failure.

The heart undergoes a major metabolic transition after birth, a change largely caused by alterations in substrate availability, hormone levels and transcription factor content. However, another factor that could contribute to the resulting upregulation of oxidative metabolism is the increase in taurine levels. We proposed that by increasing UUG decoding and the biosynthesis of mitochondria encoded proteins, elevations in taurine content enhance electron transport flux and increase oxidative metabolism. To test our hypothesis, the effect of reduced taurine content on oxidative metabolism of myocardial mitochondria and neonatal cardiomyocytes was examined. Taurine deficient neonatal mitochondria exhibited impaired oxidation of complex I specific- but not complex II specific-substrates, indicating that taurine deficiency regulates complex I activity. Taurine deficiency also reduced respiration of neonatal cardiomyocytes oxidizing carbohydrate (glucose, lactate and pyruvate). However, cardiomyocytes from 2-3 day-old hearts respiring either β-hydroxybutyrate, an important substrate in the neonatal heart, or palmitate, which is poorly metabolized during the early neonatal period, were resistant to the metabolic defects of taurine deficiency, These data support the hypothesis that taurine contributes to development of respiratory chain function after birth, which is required for oxidative metabolism of multiple substrates.