Mitochondrial iron sequestration in dopamine-challenged astroglia: Role ofheme oxygenase-1 and the permeability transition pore

Little is currently known concerning the mechanisms responsible for the exc essive deposition of redox-active iron in the substantia nigra of subjects with Parkinson's disease (PD), In the present study, we demonstrate that do pamine promotes the selective sequestration of non-transferrin-derived iron by the mitochondrial compartment of cultured rat astroglia and that the me chanism underlying this novel dopamine effect is oxidative in nature. We al so provide evidence that up-regulation of the stress protein heme oxygenase -1 (HO-1) is both necessary and sufficient for mitochondrial iron trapping in dopamine-challenged astroglia. Finally, we show that opening of the mito chondrial transition pore (MTP) mediates the influx of non-transferrin-deri ved iron into mitochondria of dopamine-stimulated and HO-1-transfected astr oglia, Our findings provide an explanation for the pathological iron seques tration, mitochondrial insufficiency, and amplification of oxidative injury reported in the brains of PD subjects. Pharmacological blockade of transit ion metal trapping by "stressed" astroglial mitochondria (e.g., using HO-1 inhibitors or modulators of the MTP) may afford effective neuroprotection i n patients with PD and other neurological afflictions.