Effects of propionyl-l-carnitine on isolated mitochondrial function in the reperfused diabetic rat heart (original) (raw)
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Molecular and cellular biochemistry, 2000
Previous studies have shown that propionyl-L-carnitine (PLC) can exert cardiac antiischemic effects in models of diabetes. In the nonischemic diabetic rat heart, PLC improves ventricular function secondary to stimulation in the oxidation of glucose and palmitate. Whether this increase in the oxidation of these substrates can explain the beneficial effects of PLC in the ischemic reperfused diabetic rat heart has yet to be determined. Diabetes was induced in male Sprague-Dawley rats by an intravenous injection of streptozotocin (60 mg/kg). Treatment was initiated by supplementing the drinking water with propionyl-L-carnitine at the concentration of 1 g/L. After a 6-week treatment period, exogenous substrate oxidation and recovery of mechanical function following ischemia were determined in isolated working hearts. In aerobically perfused diabetic hearts, compared with those of controls, rates of glucose oxidation were lower, but those of palmitate oxidation were similar. Diabetes was ...
FEBS Letters, 1999
The effect of aging and acute treatment with acetyl-Lcarnitine on the pyruvate transport and oxidation in rat heart mitochondria was studied. The activity of the pyruvate carrier as well as the rates of pyruvate-supported respiration were both depressed (around 40%) in heart mitochondria from aged rats, the major decrease occurring during the second year of life. Administration of acetyI-L-carnitine to aged rats almost completely restored the rates of these metabolic functions to the level of young control rats. This effect of acetyl-L-carnitine was not due to changes in the content of pyruvate carrier molecules. The heart mitochondrial content of cardiolipin, a key phospholipid necessary for mitochondrial substrate transport, was markedly reduced (approximately 40%) in aged rats. Treatment of aged rats with acetyl-L-carnitine reversed the age-associated decline in cardiolipin content. As the changes in cardiolipin content were correlated with changes in rates of pyruvate transport and oxidation, it is suggested that acetyl-Lcarnitine reverses the age-related decrement in the mitochondrial pyruvate metabolism by restoring the normal cardiolipin content.
Stimulation of Non-oxidative Glucose Utilization by?-carnitine in Isolated Myocytes
Journal of Molecular and Cellular Cardiology, 1995
S. A-, M. S-A, M. A. N, S. C. H, J. S. L J. E. L. Stimulation of Non-oxidative Glucose Utilization by -carnitine in Isolated Myocytes. Journal of Molecular and Cellular Cardiology (1995) 27, 2465-2472. The effects of -carnitine on 14 CO 2 release from [1-14 C]pyruvate oxidation (an index of pyruvate dehydrogenase activity, PDH), [2-14 C]pyruvate, and [6-14 C]glucose oxidation (indices of the acetyl-CoA flux through citric acid cycle), and [U -14 C]glucose (an index of both PDH activity and the flux of acetyl-CoA through the citric acid cycle), were studied using isolated rat cardiac myocytes. -carnitine increased the release of 14 CO 2 from [1-14 C]pyruvate, and decreased that of [2-14 C]pyruvate in a time and concentration-dependent manner. At a concentration of 2.5 m, -carnitine produced a 50% increase of CO 2 release from [1-14 C]pyruvate and a 50% decrease from [2-14 C]pyruvate oxidation. -carnitine also increased CO 2 release from [1-14 C[pyruvate oxidation by 35%, and decreased that of [2-14 C]pyruvate oxidation 30%, in isolated rat heart mitochondria. The fatty acid oxidation inhibitor, etomoxir, stimulated the release of CO 2 from both [1-14 ]pyruvate and [2-14 C]pyruvate. These results were supported by the effects of -carnitine on the CO 2 release from [6-14 C]-and [U-14 C]glucose oxidation. -carnitine (5 m) decreased the CO 2 release from [6-14 C]glucose by 37%, while etomoxir (50 ) increased its release by 24%. -carnitine had no effect on the oxidation of [U-14 C]glucose. -carnitine increased palmitate oxidation in a time-and concentration-dependent manner in myocytes. Also, it increased the rate of efflux of acetylcarnitine generated from pyruvate in myocytes. These results suggest that -carnitine stimulates pyruvate dehydrogenase complex activity and enhances non-oxidative glucose metabolism by increasing the mitochondrial acetylcarnitine efflux in the absence of exogenous fatty acids.
Translating the basic knowledge of mitochondrial functions to metabolic therapy: role of L-carnitine
2013
Mitochondria play important roles in human physiological processes, and therefore, their dysfunction can lead to a constellation of metabolic and nonmetabolic abnormalities such as a defect in mitochondrial gene expression, imbalance in fuel and energy homeostasis, impairment in oxidative phosphorylation, enhancement of insulin resistance, and abnormalities in fatty acid metabolism. As a consequence, mitochondrial dysfunction contributes to the pathophysiology of insulin resistance, obesity, diabetes, vascular disease, and chronic heart failure. The increased knowledge on mitochondria and their role in cellular metabolism is providing new evidence that these disorders may benefit from mitochondrial-targeted therapies. We review the current knowledge of the contribution of mitochondrial dysfunction to chronic diseases, the outcomes of experimental studies on mitochondrial-targeted therapies, and explore the potential of metabolic modulators in the treatment of selected chronic conditions. As an example of such modulators, we evaluate the efficacy of the administration of L-carnitine and its analogues acetyl and propionyl Lcarnitine in several chronic diseases. L-carnitine is intrinsically involved in mitochondrial metabolism and function as it plays a key role in fatty acid oxidation and energy metabolism. In addition to the transportation of free fatty acids across the inner mitochondrial membrane, Lcarnitine modulates their oxidation rate and is involved in the regulation of vital cellular functions such as apoptosis. Thus, L-carnitine and its derivatives show promise in the treatment of chronic conditions and diseases associated with mitochondrial dysfunction but further translational studies are needed to fully explore their potential. The aim of our work is to review the current understanding of mitochondrial functions and dysfunctions, which may provide updated information on optimal strategies to modulate mitochondrial metabolism for clinical applications. As an example of the use of nutrients in the therapy of conditions or diseases having mitochondrial dysfunction as a common pathophysiological mechanism, we focus our attention on the metabolic compound Lcarnitine, which has well-established roles in mitochondrial metabolism.
Carnitine homeostasis, mitochondrial function and cardiovascular disease
Drug Discovery Today: Disease Mechanisms, 2009
Carnitines are involved in mitochondrial transport of fatty acids and are of critical importance for maintaining normal mitochondrial function. This review summarizes recent experimental and clinical studies showing that mitochondrial dysfunction secondary to a disruption of carnitine homeostasis may play a role in decreased NO signaling and the development of endothelial dysfunction. Future challenges include development of agents that can positively modulate Lcarnitine homeostasis which may have high therapeutic potential. 1. Introduction L-carnitine is a ubiquitously occurring trimethylated amino acid that plays an important role in the transport of long chain fatty acids across the inner mitochondrial membrane [1]. Carnitines exist either as free carnitines or as acylcarnitines (Figure 1 A). The acylcarnitines are products of the reaction in which acyl moieties are transferred to carnitine from acyl-CoA. These acyl groups vary in length from short chain (acetyl) to long chain (palmitoyl). This reaction is catalyzed by a family of enzymes known as acyltransferases. These enzymes differ on the basis of the structural specificity of the acyl group and their sub-cellular localization. Carnitine deficiency or abnormalities in the carnitine acyltransferase systems results in a reduced β-oxidation of fatty acids and therefore, reduced energy (ATP) production. Recent studies suggest that mitochondrial dysfunction, secondary to a disruption of carnitine homeostasis, may also play a role in the loss of nitric oxide (NO) signaling and the development of endothelial dysfunction associated with a variety of cardiovascular diseases [2]. 2. Carnitine Biosynthesis Carnitine in humans is derived from diet and de novo biosynthesis using lysine and methionine. The main dietary sources of carnitine are red meat, fish, and dairy products