1-methyl-4-phenylpyridinium ion (MPP+) selectively inhibits the replication of mitochondrial DNA
1-methyl-4-phenylpyridinium ion (MPP+) selectively inhibits the replication of mitochondrial DNA
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DOI：
10.1046/j.1432-1327.1999.00056.x
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发表时间：
1999-01-01
期刊：
影响因子：
--
通讯作者：
Kang, D
中科院分区：
文献类型：
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作者：
Miyako, K;Irie, T;Kang, D
已知 1-甲基-4-苯基-1,2,3,6-四氢吡啶以其神经毒性形式 1-甲基-4-苯基吡啶鎓离子 (MPP+) 会导致帕金森症。我们之前曾报道，MPP+ 会降低线粒体 DNA (mtDNA) 的含量，与人类细胞中复合物 I 的抑制无关[Miyako, K.、Kai, Y.、Irie, T.、Takeshige, K. 和 Kang, D. (1997) J. Biol.化学。 272, 9605-9608]。在这里我们研究导致mtDNA减少的机制。最大功率点+。抑制 5-bromo-2'-deoxyuridine 掺入 mtDNA，但不掺入核 DNA，表明 MPP+ 抑制 mtDNA 的复制，但不抑制核基因组的复制。 mtDNA 的复制是由轻链转录转换而来的重链合成启动的。 MPP+ 减少每个 mtDNA 的新生重链，并增加每个 mtDNA 轻链上编码的 ND6 基因的转录本。线粒体转录因子A的量没有减少。这些数据表明转录没有受到抑制，因此在 MPP+ 处理的细胞中 mtDNA 从转录到复制的转变降低。电子显微镜显示MPP+处理的细胞中线粒体的数量没有减少，表明MPP+不影响线粒体的整体生物发生。因此，MPP+选择性地抑制mtDNA的复制。
1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine is known to cause Parkinsonism in its neurotoxic form, 1-methyl-4-phenylpyridinium ion (MPP+). We have previously reported that MPP+ decreases the content of mitochondrial DNA (mtDNA) independently of the inhibition of complex I in human cells [Miyako, K., Kai, Y., Irie, T., Takeshige, K., and Kang, D. (1997) J. Biol. Chem. 272, 9605-9608]. Here we study the mechanism causing the decrease in mtDNA. MPP+. inhibits the incorporation of 5-bromo-2'-deoxyuridine into mtDNA but not into nuclear DNA, indicating that MPP+ inhibits the replication of mtDNA but not that of the nuclear genome. The replication of mtDNA is initiated by the synthesis of the heavy strand switched from the transcription of the light strand. MPP+ decreases the nascent heavy strands per mtDNA and increases the transcript of the ND6 gene, encoded on light strand, per mtDNA. The amount of mitochondrial transcription factor A is not decreased. These data suggest that the transcription is not inhibited and therefore the transition from transcription to replication of mtDNA is lowered in the MPP+-treated cells. Electron microscopy shows that the number of mitochondria is not decreased in the MPP+- treated cells, suggesting that MPP+ does not affect the overall biogenesis of mitochondria. Thus, MPP+ selectively inhibits the replication of mtDNA.