Role of Ca2+ and Sodium-Calcium exchanger (NCX) on cellular/mitochondrial uptake and toxicity of the parkinsonian toxin, MPP+
Although the exact cause(s) of dopaminergic cell death in Parkinson's disease (PD) is not fully understood, the discovery that 1-methyl-4-phenylpyridinium (MPP+ ) selectively destroys dopaminergic neurons and causes PD symptoms in humans and other mammals has strengthened the environmental hypothesis of PD. The current model for the toxicity of MPP+ is centered on its specific uptake into dopaminergic cells through the dopamine transporter (DAT), electrogenic accumulation into the mitochondria, inhibition of the mitochondrial complex I, leading to ATP depletion, increased reactive oxygen species (ROS) production, and apoptotic cell death. However, MPP+ is taken up into many cell types through a number of other transporters, challenging the major hypothesis of this model, that the specific dopaminergic toxicity of MPP+ is due to the specific uptake through DAT. In order to address this discrepancy, we have characterized a series of 4'-substituted MPP+ derivatives with varying hydrophilicities. The photophysical studies of these derivatives show that 4'I-MPP+ is fluorescent and can be used to localize the intracellular distribution of MPP+ . Using these novel probes, we have shown that both cellular and mitochondrial uptake of MPP+ are modulated by the cell and mitochondrial membrane potentials and found that Ca2+ play a key role in these MPP+ uptakes and toxicities. Furthermore, the effects of Ca2+ on MPP+ uptake and toxicity are mediated through mitochondrial and plasma membrane sodium calcium-exchangers (NCX) and the mitochondrial permeability transition pore (PTP). For the first time, we show that the specific mitochondrial NCX (mNCX) inhibitor, CGP37157 inhibits mitochondrial uptake of MPP+ and protects dopaminergic MN9D cells from MPP+ toxicity. Thus, these findings could be further exploited for development of pharmacological agents to protect central nervous system (CNS) dopaminergic neurons from PD-causing environmental toxins.
Thesis (Ph.D.)-- Wichita State University, Fairmount College of Liberal Arts and Sciences, Dept. of Chemistry
- Dissertations