THE CONTENT OF INTRACELLULAR MITOCHONDRIAL-DNA IS DECREASED BY 1-METHYL-4-PHENYLPYRIDINIUM ION (MPP(+))

1-Methyl-4-phenylpyridinium ion (MPP(+)), an oxidative metabolite of 1 -methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), is considered to b e directly responsible for MPTP-induced Parkinson's disease-like sympt oms by inhibiting NADH-ubiquinone oxidoreductase (complex I) in the mi tochondrial respiratory chain, Here we demonstrate that 25 mu M MPP(+) decreases the content of mitochondrial DNA to about one-third in HeLa S3 cells, On the contrary, 0.1 mu M rotenone, which inhibits complex I to the same extent as 25 mu M MPP(+) in the cells, increases the con tent of mitochondrial DNA about a-fold, Hence, the effect of MPP(+) on mitochondrial DNA is not mediated by the inhibition of complex I, To examine the replication state of mitochondrial DNA, we measured the am ount of nascent strands of mitochondrial DNA. The amount is decreased by MPP(+) but increased by rotenone, suggesting that the replication o f mitochondrial DNA is inhibited by MPP(+). Because the proper amount of mitochondrial DNA is essential to maintain components of the respir atory chain, the decrease of mitochondrial DNA may play a role in the progression of MPTP induced Parkinson's disease-like symptoms caused b y the mitochondrial respiratory failure.