El-Hattab Ayman W, Emrick Lisa T, Hsu Jean W, Chanprasert Sirisak, Almannai Mohammed, Craigen William J, Jahoor Farook, Scaglia Fernando
Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA; Division of Clinical Genetics and Metabolic Disorders, Pediatrics Department, Tawam Hospital, Al-Ain, United Arab Emirates.
Division of Neurology and Developmental Neuroscience, Baylor College of Medicine, Houston, TX, USA.
Mol Genet Metab. 2016 Apr;117(4):407-12. doi: 10.1016/j.ymgme.2016.01.010. Epub 2016 Jan 27.
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.
线粒体脑肌病伴乳酸酸中毒和卒中样发作（MELAS）综合征是最常见的母系遗传线粒体疾病之一。该综合征的发病机制尚未完全明确，据信是由多种相互作用的机制导致的，包括线粒体能量产生受损、微血管病变和一氧化氮（NO）缺乏。MELAS综合征中的NO缺乏可能源于多种因素，其中NO前体精氨酸和瓜氨酸的可用性降低起主要作用。在本研究中，我们使用稳定同位素输注技术评估MELAS综合征患儿和健康儿童对照的NO生成情况。我们还评估了口服精氨酸和瓜氨酸补充剂对MELAS综合征患儿NO生成的影响。与对照受试者相比，发现MELAS综合征患儿的NO生成、精氨酸通量、血浆精氨酸和瓜氨酸通量较低。在MELAS综合征患儿中，补充精氨酸导致NO生成、精氨酸通量和精氨酸浓度增加。补充瓜氨酸导致这些参数有更大幅度的增加。此外，补充瓜氨酸与瓜氨酸浓度和通量以及从头合成精氨酸的速率显著增加有关。瓜氨酸在增加NO生成方面的更大作用是由于其更有能力增加精氨酸的可用性，特别是在发生NO合成的细胞内区室。这项研究是首次评估线粒体疾病患儿的NO代谢，为MELAS综合征中存在NO缺乏的观点增加了更多证据，表明瓜氨酸作为NO前体的作用更大，效果更好，并表明MELAS综合征患儿和成人都存在NO生成受损的情况。因此，在生命早期开始使用NO前体进行治疗可能有益。需要进行对照临床试验来评估精氨酸和瓜氨酸对MELAS综合征临床并发症的治疗效果。
