Mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (
MELAS) syndrome is one of the most common
mitochondrial disorders. Although the pathogenesis of
stroke-like episodes remains unclear, it has been suggested that mitochondrial proliferation may result in endothelial dysfunction and decreased
nitric oxide (NO) availability leading to cerebral ischemic events. This study aimed to assess NO production in subjects with
MELAS syndrome and the effect of the NO precursors
arginine and
citrulline. Using stable
isotope infusion techniques, we assessed
arginine,
citrulline, and NO metabolism in control subjects and subjects with
MELAS syndrome before and after
arginine or
citrulline supplementation. The results showed that subjects with
MELAS had lower NO synthesis rate associated with reduced
citrulline flux, de novo
arginine synthesis rate, and plasma
arginine and
citrulline concentrations, and higher plasma
asymmetric dimethylarginine (ADMA) concentration and
arginine clearance. We conclude that the observed impaired NO production is due to multiple factors including elevated ADMA, higher
arginine clearance, and, most importantly, decreased de novo
arginine synthesis secondary to decreased
citrulline availability.
Arginine and, to a greater extent,
citrulline supplementation increased the de novo
arginine synthesis rate, the plasma concentrations and flux of
arginine and
citrulline, and NO production. De novo
arginine synthesis increased markedly with
citrulline supplementation, explaining the superior efficacy of
citrulline in increasing NO production. The improvement in NO production with
arginine or
citrulline supplementation supports their use in
MELAS and suggests that
citrulline may have a better
therapeutic effect than
arginine. These findings can have a broader relevance for other disorders marked by perturbations in NO metabolism.