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Citrulline and arginine utility in treating nitric oxide deficiency in mitochondrial disorders

https://doi.org/10.1016/j.ymgme.2012.06.018Get rights and content

Abstract

Mitochondrial diseases arise as a result of dysfunction of the respiratory chain, leading to inadequate ATP production required to meet the energy needs of various organs. On the other hand, nitric oxide (NO) deficiency can occur in mitochondrial diseases and potentially play major roles in the pathogenesis of several complications including stroke-like episodes, myopathy, diabetes, and lactic acidosis. NO deficiency in mitochondrial disorders can result from multiple factors including decreased NO production due to endothelial dysfunction, NO sequestration by cytochrome c oxidase, NO shunting into reactive nitrogen species formation, and decreased availability of the NO precursors arginine and citrulline. Arginine and citrulline supplementation can result in increased NO production and hence potentially have therapeutic effects on NO deficiency-related manifestations of mitochondrial diseases. Citrulline is a more efficient NO donor than arginine as it results in a greater increase in de novo arginine synthesis, which plays a major role in driving NO production. This concept is supported by the observation that the three enzymes responsible for recycling citrulline to NO (argininosuccinate synthase and lyase, and nitric oxide synthase) function as a complex that can result in compartmentalizing NO synthesis and channeling citrulline efficiently to NO synthesis. Clinical research evaluating the effect of arginine and citrulline in mitochondrial diseases is limited to uncontrolled open label studies demonstrating that arginine administration to subjects with MELAS syndrome results in improvement in the clinical symptoms associated with stroke-like episodes and a decrease in the frequency and severity of these episodes. Therefore, controlled clinical studies of the effects of arginine or citrulline supplementation on different aspects of mitochondrial diseases are needed to explore the potential therapeutic effects of these NO donors.

Highlights

► Nitric oxide (NO) deficiency can contribute to mitochondrial diseases complications. ► NO deficiency in mitochondrial disorders can result from multiple factors. ► Arginine and citrulline supplementation can result in increased NO production. ► Arginine and citrulline can have therapeutic effects in mitochondrial diseases. ► Controlled clinical studies of the effects of arginine or citrulline are needed.

Introduction

Mitochondrial diseases are a heterogeneous group of disorders that result from dysfunction of the mitochondrial respiratory chain. Dysfunctional mitochondria are unable to generate sufficient ATP to meet the energy needs of various tissues and organs, particularly those with high energy demand such as the central nervous system, skeletal and cardiac muscles, kidneys, liver, and endocrine systems. Other aspects of mitochondrial function such as calcium buffering, apoptosis, and retrograde signaling are also likely perturbed. Disturbed mitochondrial function in various tissues and organs can explain the multi-organ manifestations of mitochondrial diseases including epilepsy, intellectual disability, skeletal and cardiac myopathy, diabetes, sensorineural hearing loss, and renal impairment [1]. In addition to reduced energy production, there is growing evidence that nitric oxide (NO) deficiency occurs in mitochondrial diseases and can play a major role in the pathogenesis of several complications observed in mitochondrial diseases including stroke-like episodes, myopathy, diabetes, and lactic acidosis [2], [3], [4], [5], [6], [7]. The amino acids arginine and citrulline act as NO precursors and can be used to restore NO production and may be of therapeutic utility in treating NO deficiency-related manifestations of mitochondrial diseases [7].

In this article, we review the metabolic pathways of arginine, citrulline, and NO, present evidence for NO deficiency in mitochondrial diseases, discuss the possible causes of NO deficiency, review the clinical manifestations that can result from NO deficiency, and, finally, evaluate the role of arginine and citrulline supplementation in treating NO deficiency in mitochondrial disorders.

Section snippets

Arginine metabolism

l-Arginine (2-amino-5-guanidinopentanoic acid) was first isolated from lupin seedlings in 1886, and in 1895 was identified as a component of animal proteins [8]. It is an essential amino acid for young mammals, and a conditionally essential amino acid for adult humans and other animals during catabolic stress (e.g. infection or trauma) or in those with diseases involving the kidneys or small intestine (e.g. renal failure or massive small bowel resection). It is a non-essential (dispensable)

Nitric oxide deficiency in mitochondrial diseases

NO deficiency may occur in mitochondrial diseases and can play a major role in the pathogenesis of several complications, including stroke-like episodes, myopathy, diabetes, and lactic acidosis. It has been shown that patients with MELAS (mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes) syndrome have lower concentrations of NO metabolites (nitrite and nitrate, NOx) during stroke-like episodes [3], [5]. Furthermore, the NO synthesis rate as measured by stable isotope

The utility of arginine and citrulline in treating NO deficiency in mitochondrial diseases

Arginine supplementation, an essential component in the treatment of urea cycle defects, has also been examined in several other disorders, including vascular diseases, glutaric aciduria type I, and creatine transporter deficiency [46]. Citrulline supplementation has been used in OTC deficiency and short bowel syndrome [12]. For mitochondrial diseases, arginine and citrulline supplementation has only been evaluated in MELAS syndrome [3], [5], [7].

Conclusions

NO deficiency in mitochondrial disorders can result from multiple interrelated factors. Both arginine and citrulline act as NO precursors; therefore their administration can result in increased NO availability and hence may have therapeutic effects on NO deficiency-related manifestations of mitochondrial disease. Citrulline supplementation can raise NO production to a greater extent than that associated with arginine due to the substantial increase in the de novo arginine synthesis rate

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