Inhibition of mitochondrial DNA replication by MPP+, a Parkinsonism-inducing toxin

MPP（一种帕金森病诱导毒素）对线粒体 DNA 复制的抑制

• 批准号: 11670144
• 负责人: KANG Dongchon
• 金额: $ 2.3万
• 依托单位: KYUSHU UNIVERSITY
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 1999
• 资助国家: 日本
• 起止时间: 1999 至 2000
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-11670144/
• 关键词: mitochondrial DNA; MPP+; Parkinson; DNA replication; Oxidative damage of DNA; hMTH1; 酸化障害; DNA修復

Inhibition of mitochondrial DNA replication and resolution of D-loop by MPP+ 1-Methyl-4-phenylpyridinium ion (MPP+) selectively accumulates in substantia nygral cells, thereby causing Parkinsonism. We found that MPP+ selectively inhibits mitochondrial DNA replication but not nuclear DNA replication. The decrease in mitochondrial DNA by the inhibition of mitochondrial DNA replication can be a mechanism by which mitochondrial functions are impaired. MPP+ does not inhibit DNA polymerase γ that is a DNA polymerase responsible for mitochondrial DNA replication. On the other hand MPP+ rapidly depletes nascent strands of mitochondrial DNA in vivo and in oraganello. The decrease in the nascent strands is observed as early as 1 min after the addition of MPP+ in organello, strongly suggesting that MPP+ acts on an early step of mitochondrial DNA replication. We found that MPP+ inhibits the replication by ever unknown mechanism. ie., MPP+ resolves mitochondrial D-loop structure, a mitochondria DNA specific replication intermediate. Furthermore we have found that the resolution is due to the forced change by MPP+ in conformation of a brabched structure contained in the D-loop.

MPP+ 1-甲基-4-苯基吡啶离子（MPP+）对线粒体DNA复制的抑制和D-loop的分解选择性积累在神经质细胞中，从而引起帕金森病。我们发现MPP+选择性抑制线粒体DNA复制，但不抑制核DNA复制。抑制线粒体DNA复制导致的线粒体DNA减少可能是线粒体功能受损的一种机制。MPP+不抑制DNA聚合酶γ，这是一种负责线粒体DNA复制的DNA聚合酶。另一方面，MPP+在体内和内脏中迅速消耗线粒体DNA的新生链。在细胞器中加入MPP+后1分钟就观察到新生链的减少，这强烈表明MPP+在线粒体DNA复制的早期阶段起作用。我们发现MPP+通过未知的机制抑制复制。ie。MPP+分解线粒体d环结构，线粒体DNA特异性复制中间体。此外，我们还发现，分辨率是由于MPP+在d环中包含的分枝结构构象中的强迫变化。

项目成果

K.Miyako, C.Takamatsu, S.Umeda, T.Tajiri, M.Furuichi, Y.Nakabeppu, M.Sekiguchi, N.Hamasaki, K.Takeshige and D.Kang: "Accumulation of adenine DNA glycosylase-sensitive sites in human mitochondrial DNA"J.Biol.Chem.. 275. 12326-12330 (2000)

K.Miyako、C.Takamatsu、S.Umeda、T.Tajiri、M.Furuichi、Y.Nakabeppu、M.Sekiguchi、N.Hamasaki、K.Takeshige 和 D.Kang：“腺嘌呤 DNA 糖基化酶敏感位点的积累

Ide,T. et al: "Mitochondrial DNA damage and dysfunction associated with oxidative stress in failing hearts following myocardial infarction"Circ.Res.. (in press). (2001)

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Nishioka, K.：“由选择性剪接的 OGG1 mRNA 编码的两种主要形式的人 8-氧代鸟嘌呤 DNA 糖基化酶的表达和差异细胞内定位”Mol。

康東天: "ミトコンドリアゲノムの維持と疾患"福岡医学雑誌. 44. 284-290 (2000)

康东十：“线粒体基因组维护与疾病”福冈医学杂志44。284-290（2000）。

T.Ide, H.Tsutsui, S.Kinugawa, H.Utsumi, D.Kang, N.Hattori, K.Uchida, K.Arimura, K.Egashira and A.Takeshita: "Mitochondrial electron transport complex I is the potential source of oxygen free radicals in the failing myocardium"Circ.Res.. 85. 357-363 (1999)

T.Ide、H.Ttsutsui、S.Kinugawa、H.Utsumi、D.Kang、N.Hattori、K.Uchida、K.Arimura、K.Egashira 和 A.Takeshita：“线粒体电子传递复合体 I 是潜在来源