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1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), its metabolite cyperquat (MPP+) and energy transduction in
J H Thakar1, M N Hassan, J D Grimes
1Parkinson's Disease Laboratory, Ottawa Civic Hospital, Ontario, Canada.
Abstract:
In vitro studies with rat striatal and liver mitochondria have shown that the neurotoxic compound MPTP (0.5 mM) has very little effect on mitochondrial energy transduction. With pyruvate-malate (P/M), mitochondria from striatum and liver exhibited state 3 oxygen consumption rates of 101.5 +/- 21.3 and 53.6 +/- 14.8, respectively. On the other hand, MPP+ (0.5 mM) inhibited the NAD-linked substrate (P/M) oxidation in both tissue preparations. MPP+ failed to influence oxidative phosphorylation when succinate was used as the substrate. Mitochondria from liver and striatum exhibited low levels of 45Ca uptake in the absence of Mg.ADP. This was increased by about 3-fold in the presence of Mg.ADP. MPP+ under either condition had very little effect on 45Ca uptake by these organelles.
Insights
The neurotoxin MPP+, not MPTP, impairs mitochondrial energy production in rat brain and liver cells. Calcium uptake by mitochondria was unaffected by MPP+ in this in vitro study.
Area of Science:
- Biochemistry
- Neuroscience
- Toxicology
Background:
- Mitochondrial dysfunction is implicated in neurodegenerative diseases.
- MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine) is a neurotoxin that causes Parkinsonism.
- MPTP is metabolized to MPP+ (1-methyl-4-phenylpyridinium), the active toxic species.
Purpose of the Study:
- To investigate the effects of MPTP and MPP+ on mitochondrial energy transduction.
- To examine the impact of these compounds on calcium uptake in isolated mitochondria.
Main Methods:
- In vitro studies using isolated mitochondria from rat striatum and liver.
- Measurement of oxygen consumption rates (state 3) with pyruvate-malate (NAD-linked) and succinate (FAD-linked) substrates.
- Assessment of 45Ca uptake in the presence and absence of Mg.ADP.
Main Results:
- MPTP showed minimal effects on mitochondrial energy transduction.
- MPP+ significantly inhibited NAD-linked substrate oxidation (pyruvate-malate) in both striatal and liver mitochondria.
- MPP+ did not affect oxidative phosphorylation with succinate.
- MPP+ had negligible effects on 45Ca uptake by mitochondria, even with Mg.ADP.
Conclusions:
- MPP+ directly impairs mitochondrial energy metabolism via inhibition of NAD-linked substrate oxidation.
- The neurotoxic effects of MPTP likely involve the inhibition of mitochondrial respiration by its metabolite, MPP+.
- MPP+ does not appear to significantly disrupt mitochondrial calcium handling in vitro.