The D-loop structure of human mtDNA is destabilized directly by 1- methyl-4-phenylpyridinium ion (MPP+), a parkinsonism-causing toxin

Shuyo Umeda, Tsuyoshi Muta, Takashi Ohsato, Chihiro Takamatsu, Naotaka Hamasaki, Dongchon Kang

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Abstract

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine has been reported to cause parkinsonism via its neurotoxic form, 1-methyl-4-phenylpyridinium ion (MPP+), which inhibits complex I of the mitochondrial respiratory chain. Its parkinsonism-causing mechanisms attract a great deal of interest as a model of the disease. Recently, we reported that MPP+ strongly decreases the amount of mtDNA independent of the inhibition of complex I. Maintenance of a proper amount of mtDNA is essential for the normal function of mitochondria as exemplified in many mitochondrial diseases. The most characteristic feature in vertebral mtDNA replication is that H-strand synthesis proceeds displacing the parental H-strand as a long single strand. It forms the D- loop, a triplex replication intermediate composed of the parental L-strand, nascent H-strand and displaced H-strand. Here we show that MPP+ does not inhibit DNA synthesis by DNA polymerase γ, but rather releases the nascent H-strands from mtDNA both in organello and in vitro. This indicates that MPP+ directly destabilizes the D-loop structure, thereby inhibiting replication. This study raises a new mechanism, i.e. destabilization of replication intermediates, for depletion of mtDNA.

Original languageEnglish
Pages (from-to)200-206
Number of pages7
JournalEuropean Journal of Biochemistry
Volume267
Issue number1
DOIs
Publication statusPublished - Jan 17 2000

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All Science Journal Classification (ASJC) codes

  • Biochemistry

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