Koga Yasutoshi, Povalko Nataliya, Nishioka Junko, Katayama Koujyu, Yatsuga Shuichi, Matsuishi Toyojiro
Department of Pediatrics and Child Health, Kurume University Graduate School of Medicine, Kurume, Japan.
Biochim Biophys Acta. 2012 May;1820(5):608-14. doi: 10.1016/j.bbagen.2011.09.005. Epub 2011 Sep 14.
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.
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.
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.
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.
线粒体肌病、脑病、乳酸性酸中毒和卒中样发作（MELAS）中出现的卒中样发作的致病机制尚未阐明。约80%的MELAS患者线粒体tRNA（Leu（UUR））基因存在A3243G突变，这是tRNA（Leu（UUR））基因共有结构中第14位的碱基变化。
本综述旨在概述线粒体细胞病致病机制在分子水平的实际知识、线粒体血管病在临床和病理生理水平导致卒中样发作的可能致病机制，以及L-精氨酸治疗MELAS的作用位点。
分子发病机制主要通过ρ（0）细胞杂交系统证实。该突变导致蛋白质合成缺陷，原因包括：1）tRNA（Leu（UUR））分子稳态量的寿命缩短；2）氨酰基-tRNA（Leu（UUR））与未负载tRNA（Leu（UUR））分子的比例降低；3）亮氨酸氨酰化积累而无任何错酰化；4）加工中间体如RNA 19的积累；5）摆动修饰缺陷。所有这些功能丧失异常都是细胞或器官在建立表型时对线粒体能量需求的阈值效应所致。线粒体血管病通过肌肉或脑病理学表现为SSV（SDH强染色血管），并通过使用FMD（血流介导的扩张）的血管生理学表现出来。MELAS患者由于血浆L-精氨酸水平低和/或呼吸链功能障碍，表现出NO依赖性血管舒张能力下降。虽然MELAS中卒中样发作的潜在机制尚未完全了解，但L-精氨酸治疗改善了内皮功能障碍。
虽然线粒体tRNA（Leu（UUR））基因的A3243G或T3271C突变的分子发病机制已被阐明为线粒体细胞病，但MELAS中卒中样发作的潜在机制尚未完全了解。此时，L-精氨酸治疗在治疗MELAS中的卒中样发作方面显示出前景。本文是名为“线粒体生物化学”的特刊的一部分。
