Iron-sulfur enzyme mediated mitochondrial superoxide toxicity in experimental Parkinson's disease.
Mitochondrial oxidative stress is thought to be an important pathological mediator of neuronal death in Parkinson's disease. However, the precise mechanism by which mitochondrial oxidative stress mediates the death of dopaminergic neurons of the substantia nigra remains unclear. We tested the idea that neuronal damage in the MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine) model of Parkinson's disease results, in part, from superoxide radical toxicity via inactivation of an iron-sulfur (Fe-S) protein, mitochondrial aconitase. Administration of MPTP in mice resulted in inactivation of mitochondrial aconitase, but not fumarase in the substantia nigra. MPTP treatment mobilized an early mitochondrial pool of iron detectable by bleomycin chelation that coincided with mitochondrial aconitase inactivation. MPTP-induced mitochondrial aconitase inactivation, iron accumulation and dopamine depletion were significantly attenuated in transgenic mice overexpressing mitochondrial Sod2 and exacerbated in partial deficient Sod2 mice. These results suggest that mitochondrial aconitase may be an important early source of mitochondrial iron accumulation in experimental Parkinson's disease, and that superoxide radical toxicity manifested by oxidative inactivation of mitochondrial aconitase may play a pathogenic role in Parkinson's disease.
Department of Pharmaceutical Sciences, University of Colorado Health Sciences Center, Colorado, USA.
Li-Ping
LP
Liang
Manisha
M
Patel
D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine / Q000378:metabolism / Q000494:pharmacology; D000154:Aconitate Hydratase / Q000378:metabolism; D000367:Age Factors; D000818:Animals; D015153:Blotting, Western / Q000379:methods; D002851:Chromatography, High Pressure Liquid / Q000379:methods; D004298:Dopamine / Q000378:metabolism; D042967:Electron Transport Complex I / Q000378:metabolism; D005295:Ferrocyanides; D007501:Iron / Q000378:metabolism; D007506:Iron-Sulfur Proteins / Q000502:physiology*; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism*; D009474:Neurons / Q000187:drug effects* / Q000502:physiology; D020734:Parkinsonian Disorders / Q000378:metabolism*; D013482:Superoxide Dismutase / Q000235:genetics / Q000378:metabolism; D013481:Superoxides / Q000633:toxicity*; D013997:Time Factors; D000099156:Superoxide Dismutase 2
D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; D000154:Aconitate Hydratase; D004298:Dopamine; D042967:Electron Transport Complex I; D005295:Ferrocyanides; D007501:Iron; D007506:Iron-Sulfur Proteins; D013482:Superoxide Dismutase; D013481:Superoxides; D000099156:Superoxide Dismutase 2; C020354:hexacyanoferrate II