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Mitochondrial Iron Sequestration in Dopamine‐Challenged Astroglia: Role of Heme Oxygenase‐1 and the Permeability Transition Pore
Author(s) -
Schipper H. M.,
Bernier L.,
Mehindate K.,
Frankel D.
Publication year - 1999
Publication title -
journal of neurochemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.75
H-Index - 229
eISSN - 1471-4159
pISSN - 0022-3042
DOI - 10.1046/j.1471-4159.1999.0721802.x
Subject(s) - dopamine , substantia nigra , oxidative stress , mitochondrion , mitochondrial permeability transition pore , transferrin , neuroprotection , chemistry , heme oxygenase , microbiology and biotechnology , oxidative phosphorylation , heme , biochemistry , biology , dopaminergic , pharmacology , neuroscience , programmed cell death , enzyme , apoptosis
Little is currently known concerning the mechanisms responsible for the excessive deposition of redox‐active iron in the substantia nigra of subjects with Parkinson's disease (PD). In the present study, we demonstrate that dopamine promotes the selective sequestration of non‐transferrin‐derived iron by the mitochondrial compartment of cultured rat astroglia and that the mechanism underlying this novel dopamine effect is oxidative in nature. We also 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 mitochondrial transition pore (MTP) mediates the influx of non‐transferrin‐derived iron into mitochondria of dopamine‐stimulated and HO‐1‐transfected astroglia. Our findings provide an explanation for the pathological iron sequestration, mitochondrial insufficiency, and amplification of oxidative injury reported in the brains of PD subjects. Pharmacological blockade of transition metal trapping by “stressed” astroglial mitochondria (e.g., using HO‐1 inhibitors or modulators of the MTP) may afford effective neuroprotection in patients with PD and other neurological afflictions.