Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0162671 (MELAS)
 587 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

L-citrulline, classified as a nonessential amino acid, is synthesized predominantly via Delta-1-pyrroline carboxylate synthase in the endothelial cells of the small intestine. In mammals, small quantities of citrulline are also produced in nitric oxide synthase-expressing cells. Considering the fact that the enzymes involved in the endogenous synthesis of L-citrulline are all located in the mitochondria and the fact that citrulline is a component of the citrulline-nitric oxide (NO) cycle, we hypothesized that the distinct clinical, biochemical, and morphological characteristics of MELAS, a maternally inherited mitochondrial disorder, might be due to alterations in nitric oxide homeostasis. Analysis of serum from MELAS patients showed that levels of plasma arginine were similar in both patients and in controls. However, levels of citrulline in MELAS patients were significantly lower than in controls, and there was a clear inverse correlation between arginine and citrulline levels in these patients. We found no correlation between the level of heteroplasmy and the plasma levels of either arginine or citrulline. We discuss the depressed citrulline levels in MELAS patients, who have an unusual and paradoxical pattern of vascular respiratory chain expression, in the context of NO homeostasis.
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PMID:Hypocitrullinemia in patients with MELAS: an insight into the "MELAS paradox". 1576 Jun 38

Mitochondrial diseases arise as a result of dysfunction of the respiratory chain, leading to inadequate ATP production required to meet the energy needs of various organs. On the other hand, nitric oxide (NO) deficiency can occur in mitochondrial diseases and potentially play major roles in the pathogenesis of several complications including stroke-like episodes, myopathy, diabetes, and lactic acidosis. NO deficiency in mitochondrial disorders can result from multiple factors including decreased NO production due to endothelial dysfunction, NO sequestration by cytochrome c oxidase, NO shunting into reactive nitrogen species formation, and decreased availability of the NO precursors arginine and citrulline. Arginine and citrulline supplementation can result in increased NO production and hence potentially have therapeutic effects on NO deficiency-related manifestations of mitochondrial diseases. Citrulline is a more efficient NO donor than arginine as it results in a greater increase in de novo arginine synthesis, which plays a major role in driving NO production. This concept is supported by the observation that the three enzymes responsible for recycling citrulline to NO (argininosuccinate synthase and lyase, and nitric oxide synthase) function as a complex that can result in compartmentalizing NO synthesis and channeling citrulline efficiently to NO synthesis. Clinical research evaluating the effect of arginine and citrulline in mitochondrial diseases is limited to uncontrolled open label studies demonstrating that arginine administration to subjects with MELAS syndrome results in improvement in the clinical symptoms associated with stroke-like episodes and a decrease in the frequency and severity of these episodes. Therefore, controlled clinical studies of the effects of arginine or citrulline supplementation on different aspects of mitochondrial diseases are needed to explore the potential therapeutic effects of these NO donors.
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PMID:Citrulline and arginine utility in treating nitric oxide deficiency in mitochondrial disorders. 2281 33

Mitochondria are found in all nucleated human cells and generate most of the cellular energy. Mitochondrial disorders result from dysfunctional mitochondria that are unable to generate sufficient ATP to meet the energy needs of various organs. Mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS) syndrome is a frequent maternally inherited mitochondrial disorder. There is growing evidence that nitric oxide (NO) deficiency occurs in MELAS syndrome and results in impaired blood perfusion that contributes significantly to several complications including stroke-like episodes, myopathy, and lactic acidosis. Both arginine and citrulline act as NO precursors and their administration results in increased NO production and hence can potentially have therapeutic utility in MELAS syndrome. Citrulline raises NO production to a greater extent than arginine, therefore, citrulline may have a better therapeutic effect. Controlled studies assessing the effects of arginine or citrulline supplementation on different clinical aspects of MELAS syndrome are needed.
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PMID:Mitochondria: role of citrulline and arginine supplementation in MELAS syndrome. 2441 47

Mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS) syndrome is one of the most frequent maternally inherited mitochondrial disorders. The pathogenesis of this syndrome is not fully understood and believed to result from several interacting mechanisms including impaired mitochondrial energy production, microvasculature angiopathy, and nitric oxide (NO) deficiency. NO deficiency in MELAS syndrome is likely to be multifactorial in origin with the decreased availability of the NO precursors, arginine and citrulline, playing a major role. In this study we used stable isotope infusion techniques to assess NO production in children with MELAS syndrome and healthy pediatric controls. We also assessed the effect of oral arginine and citrulline supplementations on NO production in children with MELAS syndrome. When compared to control subjects, children with MELAS syndrome were found to have lower NO production, arginine flux, plasma arginine, and citrulline flux. In children with MELAS syndrome, arginine supplementation resulted in increased NO production, arginine flux, and arginine concentration. Citrulline supplementation resulted in a greater increase of these parameters. Additionally, citrulline supplementation was associated with a robust increase in citrulline concentration and flux and de novo arginine synthesis rate. The greater effect of citrulline in increasing NO production is due to its greater ability to increase arginine availability particularly in the intracellular compartment in which NO synthesis takes place. This study, which is the first one to assess NO metabolism in children with mitochondrial diseases, adds more evidence to the notion that NO deficiency occurs in MELAS syndrome, suggests a better effect for citrulline because of its greater role as NO precursor, and indicates that impaired NO production occurs in children as well as adults with MELAS syndrome. Thus, the initiation of treatment with NO precursors may be beneficial earlier in life. Controlled clinical trials to assess the therapeutic effects of arginine and citrulline on clinical complications of MELAS syndrome are needed.
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PMID:Impaired nitric oxide production in children with MELAS syndrome and the effect of arginine and citrulline supplementation. 2685 Oct 65

Mitochondrial disorders result from dysfunctional mitochondria that are unable to generate sufficient energy to meet the needs of various organs. Mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS) syndrome is one of the most frequent maternally inherited mitochondrial disorders. There is growing evidence that nitric oxide (NO) deficiency occurs in MELAS syndrome and results in impaired blood perfusion that contributes significantly to several complications in this disease. NO is synthesized from arginine by NO synthase, which catalyzes the conversion of arginine to NO and citrulline. Citrulline can be recycled into arginine, and therefore, both arginine and citrulline support NO synthesis. The use of 15N2-arginine and 13C-,2H4-citrulline stable isotope infusion allows measuring arginine flux; citrulline flux; citrulline-to-arginine flux, which represents the de novo arginine synthesis rate; and arginine-to-citrulline flux, which represents the NO production rate. The objective of this review is to highlight the utility of this method in providing additional evidence for NO deficiency in MELAS syndrome, adding more insight into the potential mechanisms of NO deficiency in this syndrome, and allowing for the assessment of the effects of supplementation with the NO donors, arginine and citrulline, on improving NO production in MELAS syndrome.
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PMID:Assessment of Nitric Oxide Production in Mitochondrial Encephalomyopathy, Lactic Acidosis, and Stroke-Like Episodes Syndrome with the Use of a Stable Isotope Tracer Infusion Technique. 2851 63

MELAS (mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes) syndrome is a maternally inherited mitochondrial disease with a broad spectrum of manifestations. In addition to impaired energy production, nitric oxide (NO) deficiency occurs in MELAS syndrome and leads to impaired blood perfusion in microvasculature that can contribute to several complications including stroke-like episodes, myopathy, and lactic acidosis. The supplementation of NO precursors, L-arginine and L-citrulline, increases NO production and hence can potentially have therapeutic utility in MELAS syndrome. L-citrulline raises NO production to a greater extent than L-arginine; therefore, L-citrulline may have a better therapeutic effect. The clinical effect of L-citrulline has not yet been studied and clinical studies on L-arginine, which are limited, only evaluated the stroke-like episodes aspect of the disease. Controlled studies are still needed to assess the clinical effects of L-arginine and L-citrulline on different aspects of MELAS syndrome.
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PMID:Arginine and citrulline for the treatment of MELAS syndrome. 2873 35

Supplemental arginine has shown promise as a safe therapeutic option to improve endogenous nitric oxide (NO) regulation in cardiovascular diseases associated with endothelial dysfunction. In clinical studies in adults, L-arginine, an endogenous amino acid, was reported to improve cardiovascular function in hypertension, pulmonary hypertension, preeclampsia, angina, and MELAS (mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes) syndrome. L-citrulline, a natural precursor of L-arginine, is more bioavailable than L-arginine because it avoids hepatic first-pass metabolism and has a longer circulation time. Although not yet well-studied, arginine/citrulline has immense therapeutic potential in some life-threatening diseases in children. However, the optimal clinical development of arginine or citrulline in children requires more information about pharmacokinetics and exposure-response relationships at appropriate ages and under relevant disease states. This article summarizes the preclinical and clinical studies of arginine/citrulline in both adults and children, including currently available pharmacokinetic information. The pharmacology of arginine/citrulline is confounded by several patient-specific factors such as variations in baseline arginine/citrulline due to developmental ages and disease states. Currently available pharmacokinetic studies are insufficient to inform the optimal design of clinical studies, especially in children. Successful bench-to-bedside clinical translation of arginine supplementation awaits information from well-designed pharmacokinetic/pharmacodynamic studies, along with pharmacometric approaches.
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PMID:Therapeutic Potential of Citrulline as an Arginine Supplement: A Clinical Pharmacology Review. 3214 Sep 97