Effects of 1‐Methyl‐4‐Phenyl‐1,2,3,6‐Tetrahydropyridine and 1‐Methyl‐4‐Phenylpyridinium Ion on Activities of the Enzymes in the Electron Transport System in Mouse Brain

Abstract

The effects of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) and 1-methyl-4-phenylpyridinium ion (MPP+) on activities of enzyme complexes in the electron transport system were studied using isolated mitochondrial preparations from C57BL/6J mouse brains. Both MPTP and MPP+ dose-dependently inhibited activity of NADH-ubiquinone oxidoreductase (EC 1.6.5.3). The inhibition was reversible. Preincubation of freeze-thawed mitochondria with MPTP or MPP+ had no effect on the inhibition; however, when nonfrozen mitochondria were used, NADH-ubiquinone oxidoreductase activity was reduced to 46% of that in the nonincubated sample after a 5-min preincubation with MPTP and to 77% of that in the nonincubated sample after a 5-min preincubation with MPP+. Kinetic analyses revealed that inhibition of MPTP was noncompetitive and that of MPP+ uncompetitive with respect to NADH. On the other hand, inhibition of MPTP was uncompetitive and that of MPP+ noncompetitive with respect to ubiquinone. Succinate-ubiquinone oxidoreductase (complex II), dihydroubiquinone-cytochrome c oxidoreductase (complex III), and ferrocytochrome c-oxygen oxidoreductase (EC 1.9.3.1) activities were either slightly inhibited or not inhibited by MPTP or MPP+. The significance of these findings is discussed in relation to the mechanism of MPTP-induced neuronal degeneration.

Effects of MPTP, MPP+ and paraquat on mitochondrial potential and oxidative stress

“…The effects of MPp+ then, differ from those of the structurally similar paraquat. The depression of mitochondrial potential by MPp+ is in accord with its selective uptake by mitochondria (17,39) and its subsequent ability to disturb enzymes critical for electron transport ( 16,19). Failure of MPp+ to promote peroxidation has been previously described (14,15).…”

“…The effect of paraquat was more pronounced in the presence of Fe-ADP, as described by Sata (31) while MPp+ had no significant effect on lipid peroxidation in either the presence nor the absence of Fe-ADP. The use of millimolar concentrations of MPp+ is validated by parallel concentrations reached in vivo within neurons accumulating this material (32), and permits our data to be related to those of several other groups using this concentration (14,19,33).…”

“…Such inhibition may largely involve NADH-linked mitochondrial oxidation (16) (17), and has been shown to occur in synaptosomal mitochondria (18). The susceptible enzyme within the respiratory chain may be the ubiquinone-linked NADH-cytochrome C reductase (Complex I) (19). Evidence supporting a mitochondrial site of action is that this organelle strongly accumulated MPp+ (17).…”

A Guide to Neurotoxic Animal Models of Parkinson's Disease

“…MPP þ is released from the nigral and striatal astrocytes through the organic cation transporter 3 into the extracellular space (Cui et al 2009;Rappold and Tieu 2010) where it is taken up by the neighboring dopaminergic neurons and terminals through the dopamine transporter. Once accumulated in dopaminergic neurons, MPP þ induces neurotoxicity primarily by inhibiting complex I of the mitochondrial electron transport chain, resulting in ATP depletion and increased oxidative stress Mizuno et al 1987).…”

Mitochondrial medicine – recent advances

“…The neurotoxin MPTP is selectively taken up by dopaminergic neurones and causes Parkinsonism in humans [87], primates and other mammals [88]. MPTP is metabolized to MPP + , which selectively inhibits the function of complex I and also causes a decrease in mtDNA copy number [88,89]. Certain mtDNA polymorphisms have been reported to be associated with an increased risk for developing Parkinson's disease [90].…”