Endothelial Dysfunction and the Effect of Arginine and Citrulline Supplementation in Children and Adolescents With Mitochondrial Diseases

BACKGROUND: In addition to the reduced energy production, characteristic of mitochondrial disorders, nitric oxide (NO) deficiency can occur as well. The NO produced by vascular endothelial cells relaxes vascular smooth muscles, resulting in vasodilation that maintains the patency of small blood vessels and promotes blood flow through microvasculature. Endothelial dysfunction due to inability of vascular endothelium to generate enough NO to maintain adequate vasodilation can result in decreased perfusion in the microvasculature of various tissues, contributing to many complications seen in individuals with mitochondrial diseases. The amino acids arginine and citrulline are NO precursors: increasing their concentrations could potentially restore NO production. METHODS: In this study, we assessed endothelial dysfunction in children and adolescents with mitochondrial diseases. We also investigated the effect of arginine and citrulline supplementation on endothelial dysfunction in these individuals. We used peripheral arterial tonometry to measure the reactive hyperemic index (RHI), which is low when there is endothelial dysfunction. RESULTS: The results demonstrated low RHI in individuals with mitochondrial diseases, indicating endothelial dysfunction. RHI increased with arginine or citrulline supplementation suggesting that supplementation with NO precursors can improve endothelial dysfunction by enhancing NO production. CONCLUSIONS: This study is the first one to use peripheral arterial tonometry methodology in mitochondrial diseases. The results of this study provide evidence for endothelial dysfunction in mitochondrial diseases and demonstrate that arginine or citrulline supplementation can alleviate the endothelial dysfunction, providing more evidence for the potential therapeutic utility of these amino acids in mitochondrial diseases.