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

Mol Genet Metab. 2012 Nov;107(3):247-52. doi: 10.1016/j.ymgme.2012.06.018. Epub 2012 Jul 6.


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.

Publication types

  • Review

MeSH terms

  • Arginine / metabolism
  • Arginine / pharmacology
  • Arginine / therapeutic use*
  • Argininosuccinate Lyase / metabolism
  • Argininosuccinate Synthase / metabolism
  • Citrulline / metabolism
  • Citrulline / pharmacology
  • Citrulline / therapeutic use*
  • Clinical Trials as Topic
  • Electron Transport / drug effects
  • Electron Transport Complex IV / metabolism
  • Humans
  • MELAS Syndrome / drug therapy*
  • MELAS Syndrome / metabolism
  • MELAS Syndrome / pathology
  • Mitochondria / drug effects*
  • Mitochondria / metabolism
  • Mitochondria / pathology
  • Nitric Oxide / agonists
  • Nitric Oxide / deficiency*
  • Nitric Oxide Synthase Type III / metabolism
  • Reactive Nitrogen Species / metabolism


  • Reactive Nitrogen Species
  • Citrulline
  • Nitric Oxide
  • Arginine
  • Nitric Oxide Synthase Type III
  • Electron Transport Complex IV
  • Argininosuccinate Lyase
  • Argininosuccinate Synthase