| The neurotransmitter dopamine (DA) oxidizes through two pathways to form reactive oxygen species and DA quinones, which have been proposed to contribute to the neurodegeneration of Parkinson's disease. Previous work suggested that modification of protein sulfhydryls by DA metabolites contributes to DA-induced neuronal toxicity, but the critically affected proteins are not known. Additional evidence suggested that mitochondrial function may be decreased in Parkinson's disease. Sulfhydryl modification and oxidation can inhibit mitochondrial respiratory enzymes and can open the mitochondrial permeability transition pore, processes linked to neurodegenerative conditions. This dissertation examined whether DA oxidation products affect these mitochondrial functions, which could contribute to DA-induced toxicity and Parkinson's disease.; Both pathways of DA oxidation altered mitochondrial respiration, as measured by oxygen consumption in isolated rat brain mitochondria. DA oxidation by monoamine oxidase resulted in the inhibition of respiration linked to ATP production. The second pathway of DA oxidation, forming DA quinone, caused an increase in respiration that is uncoupled to ATP production.; DA oxidation products also exerted effects on the mitochondrial permeability transition pore. Production of DA quinone led to mitochondrial swelling, characteristic of pore opening, that was prevented by a pore inhibitor. In contrast, oxidation of DA by endogenous monoamine oxidase did not result in mitochondrial swelling.; Most studies of the pore utilize liver mitochondria, and the assumption that properties in brain mitochondria are similar had never been tested. Therefore, a direct comparison of liver and brain mitochondria was performed, and it was found that brain mitochondria did not undergo the characteristic extensive swelling, release of glutathione, or morphologic alteration observed in liver mitochondria after exposure to classic pore inducers. Because of these differences, the effect of DA quinone on liver mitochondria was investigated, and it was found that DA quinone caused large-scale swelling of liver mitochondria, similar to that observed with classic pore inducers. This provides further evidence that DA quinone induces the opening of the transition pore.; These studies show that DA oxidation products can cause dysfunction of mitochondrial respiration and can induce the opening of the permeability transition pore. These alterations may contribute to neurodegenerative conditions such as Parkinson's disease. |
