Open Access1‐Methyl‐4‐phenylpyridinium ion (MPP + ) selectively inhibits the replication of mitochondrial DNA
Author(s) -
Miyako Kenichi,
Irie Takashi,
Muta Tsuyoshi,
Umeda Shuyo,
Kai Yoichiro,
Fujiwara Toshiyuki,
Takeshige Koichiro,
Kang Dongchon
Publication year - 1999
Publication title -
european journal of biochemistry
Language(s) - English
Resource type - Journals
eISSN - 1432-1033
pISSN - 0014-2956
DOI - 10.1046/j.1432-1327.1999.00056.x
Subject(s) - mitochondrial dna , chemistry , dna replication , dna , ion , replication (statistics) , biophysics , microbiology and biotechnology , biology , biochemistry , gene , virology , organic chemistry
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.