Inhibition of mitochondrial DNA replication by MPP+, a Parkinsonism-inducing toxin

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Inhibition of mitochondrial DNA replication and resolution of D-loop by MPP+ 1-Methyl-4-phenylpyridinium ion (MPP+) selectively accumulates in substantia nygral cells, thereby causing Parkinsonism. We found that MPP+ selectively inhibits mitochondrial DNA replication but not nuclear DNA replication. The decrease in mitochondrial DNA by the inhibition of mitochondrial DNA replication can be a mechanism by which mitochondrial functions are impaired. MPP+ does not inhibit DNA polymerase γ that is a DNA polymerase responsible for mitochondrial DNA replication. On the other hand MPP+ rapidly depletes nascent strands of mitochondrial DNA in vivo and in oraganello. The decrease in the nascent strands is observed as early as 1 min after the addition of MPP+ in organello, strongly suggesting that MPP+ acts on an early step of mitochondrial DNA replication. We found that MPP+ inhibits the replication by ever unknown mechanism. ie., MPP+ resolves mitochondrial D-loop structure, a mitochondria DNA specific replication intermediate. Furthermore we have found that the resolution is due to the forced change by MPP+ in conformation of a brabched structure contained in the D-loop.