The study of mitochondrial respiratory activity, such as complex I activity, in Parkinson's disease (PD) is an exceptionally active research area that has attracted numerous investigators. Our proposal is novel, however, because it is based on 3 new observations: (l) The deficiency in mitochondrial respiration in PD is expressed by human skin fibroblasts, representing a cell type that undergoes active cell division in culture to provide a continuing supply of cells for experimentation; (2) A deficit in mitochondrial respiration can be induced in normal cells by exposure to L-dopa, an agent widely used in the treatment of idiopathic PD; (3) Ascorbate, an antioxidant, enhances mitochondrial respiratory activity in control fibroblasts and blocks the decline in activity induced by exposure to L-dopa. These observations open a new window into (a) the effect of oxidative stress in mitochondrial function and (b) the significance and regulation of complex I activity. The proposed new studies will include: Comparison of mitochondrial respiratory activity in PD with other neurological disorders and appropriate controls (Aim l); further characterization of the defect in PD (Aim 2); assessment of cellular and mitochondrial antioxidant defenses in control and PD fibroblasts (Aim 3); evaluation of susceptibility of mitochondrial respiration to oxidative stress in PD and control fibroblasts, as well as in mesencephalic cell cultures containing dopaminergic neurons (Aim 4); and evaluation of antioxidant treatment for improvement of mitochondrial respiration in fibroblasts and neuronal cell cultures (Aim 5). Our studies will provide basic information on the possible causes of deficits in mitochondrial respiration in PD and on the effects of antioxidants on mitochondrial function.
| Mytilineou, C; Kokotos Leonardi, E T; Kramer, B C et al. (1999) Glial cells mediate toxicity in glutathione-depleted mesencephalic cultures. J Neurochem 73:112-9 |
| Mytilineou, C; Leonardi, E K; Radcliffe, P et al. (1998) Deprenyl and desmethylselegiline protect mesencephalic neurons from toxicity induced by glutathione depletion. J Pharmacol Exp Ther 284:700-6 |
