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

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 pr eviously reported that MPP+ decreases the content of mitochondrial DNA (mtD NA) 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 b ut 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 l ight strand. MPP+ decreases the nascent heavy strands per mtDNA and increas es 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 transiti on from transcription to replication of mtDNA is lowered in the MPP+-treate d cells. Electron microscopy shows that the number of mitochondria is not d ecreased in the MPP+- treated cells, suggesting that MPP+ does not affect t he overall biogenesis of mitochondria. Thus, MPP+ selectively inhibits the replication of mtDNA.