Nitric Oxide Deficiency in Mitochondrial Disorders: The Utility of Arginine and Citrulline

Abstract

Mitochondrial diseases represent a growing list of clinically heterogeneous disorders that are associated with dysfunctional mitochondria and multisystemic manifestations. In spite of a better understanding of the underlying pathophysiological basis of mitochondrial disorders, treatment options remain limited. Over the past two decades, there is growing evidence that patients with mitochondrial disorders have nitric oxide (NO) deficiency due to the limited availability of NO substrates, arginine and citrulline; decreased activity of nitric oxide synthase (NOS); and NO sequestration. Studies evaluating the use of arginine in patients with mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes (MELAS) presenting with stroke-like episodes showed symptomatic improvement after acute administration as well as a reduction in the frequency and severity of stroke-like episodes following chronic use. Citrulline, another NO precursor, was shown through stable isotope studies to result in a greater increase in NO synthesis. Recent studies showed a positive response of arginine and citrulline in other mitochondrial disorders besides MELAS. Randomized-controlled studies with a larger number of patients are warranted to better understand the role of NO deficiency in mitochondrial disorders and the efficacy of NO precursors as treatment modalities in these disorders.

The Differences of Metabolites in Different Parts of the Brain Induced by Shuxuetong Injection against Cerebral Ischemia-Reperfusion and Its Corresponding Mechanism

“…Arginine administration is associated with clinical and biochemical improvement of stroke-like episodes in patients with mitochondrial disease. During stroke-like episodes in patients with mitochondrial disease, transient changes and fading were observed in brain magnetic resonance imaging (MRI) within 1 week of arginine administration [ 44 ]. Bone bridge protein peptides containing arginine, alanine, and aspartate motifs significantly reduced brain infarct volume in the MCAO model [ 45 ].…”

High‐dose oral glutamine supplementation reduces elevated glutamate levels in cerebrospinal fluid in patients with mitochondrial encephalomyopathy, lactic acidosis and stroke‐like episodes syndrome

“…Therefore, an oral supplement with this essential amino acid is recommended to treat and prevent stroke-like episodes [8]. Whether stroke-like episodes and other neurological manifestations result from an imbalance of mitochondrial energy metabolism, neuronal hyperexcitability, neuronastrocyte uncoupling, endothelial dysfunction or microvasculature mitochondrial angiopathy is disputed [8][9][10][11][12].…”

Electrolyte Disorders in Mitochondrial Cytopathies: A Systematic Review

“…For example, a deficiency of nitric oxide can lead to either sodium retention or sodium wasting, possibly depending on the specific tubular location and timing (nitric oxide has a short half-life). [107][108][109] Deficiency of nitric oxide is a hallmark of some mitochondrial diseases, 110 and it is likely to be present in other mitochondrial diseases as well because of the production of reactive oxygen species. 107 Hypothetically, different mitochondrial defects might have different effects on the production of reactive oxygen species and nitric oxide, depending on the cell type and its unique metabolic wiring, and thereby differ in the effect on electrolyte reabsorption.…”