title: Molecular pathology of MELAS and L-arginine effects.
abstract: BACKGROUND
  The pathogenic mechanism of stroke-like episodes seen in mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes (MELAS) has not been clarified yet. About 80% of MELAS patients have an A3243G mutation in the mitochondrial tRNA(Leu(UUR)) gene, which is the base change at position 14 in the consensus structure of tRNA(Leu(UUR)) gene.
  
  
  METHODS
  This review aims to give an overview on the actual knowledge about the pathogenic mechanism of mitochondrial cytopathy at the molecular levels, the possible pathogenic mechanism of mitochondrial angiopathy to cause stroke-like episodes at the clinical and pathophysiological levels, and the proposed site of action of l-arginine therapy on MELAS.
  
  
  CONCLUSIONS
  Molecular pathogenesis is mainly demonstrated using ρ(0) cybrid system. The mutation creates the protein synthesis defects caused by 1) decreased life span of steady state amount of tRNA(Leu(UUR)) molecules; 2) decreased ratio of aminoacyl-tRNA(Leu(UUR)) versus uncharged tRNA(Leu(UUR)) molecules; 3) the accumulation of aminoacylation with leucine without any misacylation; 4) accumulation of processing intermediates such as RNA 19, 5) wobble modification defects. All of these loss of function abnormalities are created by the threshold effects of cell or organ to the mitochondrial energy requirement when they establish the phenotype. Mitochondrial angiopathy demonstrated by muscle or brain pathology, as SSV (SDH strongly stained vessels), and by vascular physiology using FMD (flow mediated dilation). MELAS patients show decreased capacity of NO dependent vasodilation because of the low plasma levels of l-arginine and/or of respiratory chain dysfunction. Although the underlying mechanisms are not completely understood in stroke-like episodes in MELAS, l-arginine therapy improved endothelial dysfunction.
  
  
  CONCLUSIONS
  Though the molecular pathogenesis of an A3243G or T3271C mutation of mitochondrial tRNA(Leu(UUR)) gene has been clarified as a mitochondrial cytopathy, the underlying mechanisms of stroke-like episodes in MELAS are not completely understood. At this point, l-arginine therapy showed promise in treating of the stroke-like episodes in MELAS. This article is part of a Special Issue entitled Biochemistry of Mitochondria.
authors.affiliation: Department of Pediatrics and Child Health, Kurume University Graduate School of Medicine, Kurume, Japan. yasukoga@med.kurume-u.ac.jp
authors.forename: Yasutoshi
authors.initials: Y
authors.lastname: Koga
authors.forename: Nataliya
authors.initials: N
authors.lastname: Povalko
authors.forename: Junko
authors.initials: J
authors.lastname: Nishioka
authors.forename: Koujyu
authors.initials: K
authors.lastname: Katayama
authors.forename: Shuichi
authors.initials: S
authors.lastname: Yatsuga
authors.forename: Toyojiro
authors.initials: T
authors.lastname: Matsuishi
mesh_terms: D001120:Arginine / Q000627:therapeutic use*; D006801:Humans; D017241:MELAS Syndrome / Q000188:drug therapy* / Q000473:pathology*
chemical_list: D001120:Arginine