Open AccessThe D‐loop structure of human mtDNA is destabilized directly by 1‐methyl‐4‐phenylpyridinium ion (MPP + ), a parkinsonism‐causing toxin
Author(s) -
Umeda Shuyo,
Muta Tsuyoshi,
Ohsato Takashi,
Takamatsu Chihiro,
Hamasaki Naotaka,
Kang Dongchon
Publication year - 2000
Publication title -
european journal of biochemistry
Language(s) - English
Resource type - Journals
eISSN - 1432-1033
pISSN - 0014-2956
DOI - 10.1046/j.1432-1327.2000.00990.x
Subject(s) - mitochondrial dna , dna replication , biology , mitochondrion , dna , stereochemistry , parkinsonism , biophysics , polymerase , microbiology and biotechnology , chemistry , genetics , gene , medicine , disease , pathology
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.