Abstract
At low micromolar concentrations, 1-methyl-4-phenylpyridinium (MPP +), the toxic metabolite of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) selectively kills nigrostriatal dopaminergic neurons by mechanisms believed to involve impairment of mitochondrial complex I. A human neuroblastoma cell line expressing the dopamine transporter (DAT) was utilized to examine the effects of MPP + on acute physiologic responses and subsequent cell death. Acute responses were measured by microphysiometry and by monitoring mitochondrial membrane potential with [ 3H ]tetraphenylphosphonium (TPP +) uptake. MPP + (10 μM) increased extracellular proton excretion in DAT-expressing cells within 2–3 min, but had no effect in untransfected cells. The lipophilic complex I inhibitor, rotenone, increased proton excretion in both cell lines. In DAT-expressing cells, mitochondrial membrane potential was reduced within 1 h of 10 μM MPP + exposure. Rotenone reduced mitochondrial membrane potential in both cell lines. MPP + caused apoptotic death of DAT-transfected cells 2–3 days after drug application, but did not kill untransfected cells. Thus, MPP + produces immediate mitochondrial impairment only in cells that express DAT, and these changes occur days before overt cellular toxicity. The magnitude, time course and nature of these changes were similar to those produced by rotenone, confirming the site of action of MPP + as mitochondrial complex I. These immediate mitochondrial effects appear to be an accurate predictor of subsequent cell death.
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Disclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.