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

Nitric oxide (NO) is a free radical and a signaling molecule in several pathways, produced by nitric oxide synthase (NOS) from the conversion of L-arginine to citrulline. Supplementation of L-arginine has been used to treat MELAS (mitochondrial encephalopathy with lactic acidosis and stroke like syndrome), a mitochondrial disease caused by the m.3243A>G mutation. Low levels of serum arginine and endothelium dysfunction have been reported in MELAS and this treatment may increase NO in endothelial cells and promote vasodilation, decreasing cerebral ischemia and strokes. Although clinical benefits have been reported, little is known about NO synthesis in MELAS. In this study we found that osteosarcoma derived cybrid cells with high levels of m.3243A>G had increased nitrite, an NO metabolite, and increased intracellular NO, demonstrated by an NO fluorescent probe (DAF-FM). Muscle vessels from patients with the same mutation had increased staining in NADPH diaphorase, suggestive of increased NOS. These results indicate increased production of NO in cells harboring the m.3243A>G, however no nitrated protein was detected by Western blotting. Further studies are necessary to clarify the exact mechanisms of L-arginine effect to determine the appropriate clinical use of this drug therapy.
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PMID:Nitric oxide synthesis is increased in cybrid cells with m.3243A>G mutation. 2326 69

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