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.
Highlights
Primary mitochondrial disorders are clinically heterogeneous disorders that result from mitochondrial dysfunction caused by inherited or de novo defects in mitochondrial DNA or nuclear encoded mitochondrial genes
We have presented published evidence of nitric oxide (NO) deficiency in patients with mitochondrial disorders
We have reviewed different mechanisms leading to NO deficiency in mitochondrial disorders and how this likely leads to the various complications observed in these disorders
Summary
Primary mitochondrial disorders are clinically heterogeneous disorders that result from mitochondrial dysfunction caused by inherited or de novo defects in mitochondrial DNA (mtDNA) or nuclear encoded mitochondrial genes. Energy failure contributes to multi-organ involvement usually seen in mitochondrial disorders. While recent advances in diagnostic technologies have expanded the list of mitochondrial disorders that we know, therapeutic interventions including symptom specific therapies and supportive measures remain limited. There is growing evidence that patients with mitochondrial diseases have nitric oxide (NO) deficiency, and this can contribute to some of the complications observed in these patients. Given the myriad roles of NO as a signaling molecule, better understanding of the mechanisms of NO deficiency in mitochondrial disorders and how this deficiency can contribute to various disease manifestations will allow us to better treat these disorders. We will review the current known evidence for NO deficiency and its pathophysiology in mitochondrial diseases and the possible therapeutic interventions
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