1-Methyl-4-phenylpyridinium ion (MPP+) selectively inhibits the replication of mitochondrial DNA

Kenichi Miyako, Takashi Irie, Tsuyoshi Muta, Shuyo Umeda, Yoichiro Kai, Toshiyuki Fujiwara, Koichiro Takeshige, Dongchon Kang

Research output: Contribution to journalArticle

17 Citations (Scopus)

Abstract

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.

Original languageEnglish
Pages (from-to)412-418
Number of pages7
JournalEuropean Journal of Biochemistry
Volume259
Issue number1-2
DOIs
Publication statusPublished - Jan 15 1999

All Science Journal Classification (ASJC) codes

  • Biochemistry

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