Molecular Basis of Mitochondrial Myopathy and Animal Models Related to the Energy Abnormality

线粒体肌病的分子基础和能量异常相关的动物模型

• 批准号: 13670853
• 负责人: KOGA Yasutoshi
• 金额: $ 2.3万
• 依托单位: KURUME UNIVERSITY
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 2001
• 资助国家: 日本
• 起止时间: 2001 至 2002
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-13670853/
• 关键词: Mitochondrial stroke; endothelial dyfunction; Nitric oxide; Mitochondrial disease; mitochondrial tRNA mutation; L-arginine; RNA19; Klotho Knockout mouse

Mitochondrial myopathy is a mutisystem disorders characterized by dysfunctions of mitochondrial energy metabolism. To investigate and clarify the molecular basis of mitochondrial myopathy, the creation of animal models is essential. In 1997, Klotho gene knockout mice have been developed as a model of human aging. However, there are no reports to investigate the molecular mechanism of abnormality in the mitochondrial energy metabolism in Klotho gene knockout mice. In this project, we planned to investigate the mitochondrial energy metabolism in Klotho gene knockout mice including mitochondrial respiratory chain enzyme, cytochrome contents, oxograph, uptake of neurotransmitters in synaptosome, muscle histochemistry and mitochondrial DNA abnormalities to evaluate the relationship between aging and mitochondrial energy metabolism.MELAS, is a maternally-inherited mitochondrial multisystem disorder, characterized early onset stroke before age 20. Mitochondrial angiopathy demonstrating degene … More rative change with increased abnormal mitochondria in the endothelial cells of intramuscular small arteries and arterioles has been reported in many MELAS patients. However, the primary cause for stroke-like episodes in young MELAS patients - whether mitochondrial cytopathy, angiopathy, or both - remains controversial. Based on a hypothesis that stroke-like episodes in MELAS are caused by segmental impairment of vasodilation in intracerebral arteries, we administered L-arginine to MELAS in the acute phase of stroke. We reported that L-arginine therapy quickly improved the symptoms of stroke in MELAS, improved the microcirculation, and also reduced tissue injury from ischemia. We demonstrated the pharmacological effects of L-arginine on the acute phase of stroke-like episodes to determine whether the plasma concentrations of biological parameters including L-arginine, NOx, or ADMA, the important regulatory factors to the endothelial functions, are changed in patients with MELAS compared with normal subjects. L-arginine therapy improved the microcirculation to reduce tissue injury from ischemia, and therefore constitutes a new potential therapy for use in the acute phase of strokelike episodes in MELAS. Less

线粒体肌病是以线粒体能量代谢障碍为特征的多系统疾病。为了研究和阐明线粒体肌病的分子基础，动物模型的建立是必不可少的。1997年，Klotho基因敲除小鼠被开发为人类衰老的模型。然而，目前还没有研究Klotho基因敲除小鼠线粒体能量代谢异常的分子机制的报道。本课题通过对Klotho基因敲除小鼠线粒体呼吸链酶、细胞色素含量、血氧饱和度、突触体神经递质摄取、肌肉组织化学和线粒体DNA异常等方面的研究，探讨衰老与线粒体能量代谢的关系。MELAS是一种母系遗传的线粒体多系统疾病，在20岁之前就有早发性中风的特征表现为退行性变的线粒体血管病 ...更多信息 在许多MELAS患者中已经报道了肌内小动脉和小动脉的内皮细胞中异常线粒体增加的渐进变化。然而，年轻MELAS患者中风样发作的主要原因-是否线粒体细胞病，血管病，或两者兼而有之-仍然存在争议。基于一个假设，即MELAS中风样发作是由脑内动脉血管舒张的节段性损害引起的，我们在中风的急性期给予MELAS L-精氨酸。我们报道了L-精氨酸治疗可以迅速改善MELAS患者的中风症状，改善微循环，并减少缺血引起的组织损伤。我们证明了L-精氨酸对急性期中风样发作的药理作用，以确定是否血浆浓度的生物学参数，包括L-精氨酸，氮氧化物，或ADMA，内皮功能的重要调节因子，与正常人相比，在MELAS患者的变化。L-精氨酸治疗改善了微循环，减少了缺血引起的组织损伤，因此构成了一种新的潜在治疗方法，可用于MELAS卒中样发作的急性期。少

项目成果

Koga A, Koga Y, et al.: "Increased mitochondrial processing intermediates associated with three tRNALeu(UUR) gene mutations"Neuromuscular Dis. 13. 259-262 (2003)

Koga A、Koga Y 等人：“与三个 tRNALeu(UUR) 基因突变相关的线粒体加工中间体增加”神经肌肉疾病。

Koga Y, et al.: "Effects of L-arginine on the acute phase of strokes in three patients with MELAS"Neurology. 58. 827-828 (2002)

Koga Y 等人：“L-精氨酸对三名 MELAS 患者中风急性期的影响”神经病学。

古賀靖敏 他: "複合体III"日本臨床:増刊号「ミトコンドリアとミトコンドリア病」. 60,Suppl 4. 486-489 (2002)

Yasutoshi Koga 等：“Complex III”日本临床：特刊“线粒体和线粒体疾病”60，增刊 4. 486-489 (2002)。

古賀靖敏 他: "複合体I"日本臨床:増刊号「ミトコンドリアとミトコンドリア病」. 60,Suppl 4. 478-481 (2002)

Yasutoshi Koga 等：“Complex I”日本临床：特刊“线粒体和线粒体疾病”60，增刊 4. 478-481 (2002)。

Koga Y, et al: "Effects of L-argnine on the acute phase of strokes in three patients with MELAS"Neuromuscular Dis. 58. 827-828 (2002)

Koga Y 等人：“L-精氨酸对三名 MELAS 患者中风急性期的影响”神经肌肉疾病。