Molecular Pathology on Mitochondrial Encepholomyopathy

线粒体脑肌病的分子病理学

• 批准号: 04670151
• 负责人: OHTA Shigeo
• 金额: $ 1.34万
• 依托单位: Jichi Medical School
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for General Scientific Research (C)
• 财政年份: 1992
• 资助国家: 日本
• 起止时间: 1992 至 1993
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-04670151/
• 关键词: Mitochondria; Encepholomyopathy; Mitochondrial DNA; tRNA; Genetic Disease; Protein Synthesis; ミトコンドリアONA; ミトコンドリア; MELAS; 点変異; 培養細胞

A new mitochondrial DNA (mtDNA) mutation of tRNA^<Leu(UUR)> at nucleotide position 3271 (MELAS3271) was determined to be involved in the pathogenic process of mitochondrial diseases MELAS (mitochondrial myopathy, encephalopathy, lactic acidosis and stroke-like episodes) using intercellular transfer of patient-derived mtDNA to mtDNA-less HeLa cells (p^0 HeLa cells). Cybrid clones containing imported mtDNA exclusively from a MELAS patient with MELAS3271 mtDNA were isolated, and the influence of MELAS3271 mtDNA on mitochondrial translation activity and mitochondrial respiratory complex I enzyme activity were examined. Accumulation of more than 87% MELAS3271 mutant mtDNA in the cybrid clones induced both low complex I activity and abnormal mtDNA-encoded polypeptide synthesis including at least complex I subunit ND6, suggesting involvement of the new MELAS-associated mutation in the pathogenesis.

通过将患者来源的mtDNA转移到无mtDNA的HeLa细胞(p^0 HeLa细胞)，确定了位于3271位的tRNA^&lt；Leu(UUR)&gt；的一个新的线粒体DNA突变(MELAS3271)参与了线粒体疾病MELAS(线粒体肌病、脑病、乳酸酸中毒和卒中样发作)的发病过程。从1例携带MELAS3271 mtDNA的MELAS患者体内分离到含进口mtDNA的环状克隆，检测其对线粒体翻译活性和线粒体呼吸复合体I酶活性的影响。超过87%的MELAS3271突变体mtDNA在环状克隆中的积累导致了低的复合体I活性和至少包括复合体I亚单位ND6在内的mtDNA编码多肽的异常合成，这表明新的MELAS相关突变参与了发病机制。

项目成果

太田 成男: "ミトコンドリアDNAの遺伝情報の発現制御" 神経研究の進歩. 36. 986-992 (1992)

Shigeo Ota：“线粒体 DNA 中遗传信息表达的控制”神经学研究进展 36. 986-992 (1992)。

Matsuda S., Nakano K., Ohta S., Shimura M., Yamanaka T., Nakagawa S., Titani K.and Miyata T.: "Molecular cloning of dihydrolipoamide acetyltransferase of the rat pyruvate dehydrogenase complex : sequence comparison and evolutionary relationship to other d

Matsuda S.、Nakano K.、Ohta S.、Shimura M.、Yamanaka T.、Nakakawa S.、Titani K.和 Miyata T.：“大鼠丙酮酸脱氢酶复合物二氢硫辛酰胺乙酰转移酶的分子克隆：序列比较和进化关系

Hayashi,J-I.,他: "Accumulation of mtDNA with a mutation at position 3271 in tRNA-Leu(UUR)gene introduced from a MELAS patient to HeLa Cells lacking mtDNA results in progressive inhibition of mitochondrial respiratory function." Biochem.Biophys Res..Commun.

Hayashi, J-I. 等人：“将 MELAS 患者的 tRNA-Leu(UUR) 基因中 3271 位突变的 mtDNA 累积到缺乏 mtDNA 的 HeLa 细胞中，导致线粒体呼吸功能逐渐受到抑制。”资源。通讯。

Matsuda C., Endo H., Ohta S.and Kagawa Y.: "Gene structure of human mitochondrial ATP synthase gamma-subunit ; Tissue specificity produced by RNA splicing." J.Biol.Chem.268. 24950-24958 (1993)

Matsuda C.、Endo H.、Ohta S. 和 Kakawa Y.：“人线粒体 ATP 合酶 γ 亚基的基因结构；RNA 剪接产生的组织特异性。”

Hayashi,J-I.,他: "Accumulation of mtDNA with a mutation at position 3271 in tRNA-Leu(UUR)gene introduced from a MELAS patient to HeLa cells lacking mtDNA results in progressive inhibition of mitochondrial respiratory function." Biochem.Biophys.Res.Commun.1

Hayashi, J-I. 等人：“将 MELAS 患者的 tRNA-Leu (UUR) 基因中 3271 位突变的 mtDNA 累积到缺乏 mtDNA 的 HeLa 细胞中，导致线粒体呼吸功能逐渐受到抑制。” .Res.Commun.1