, Volume 28, Issue 2, pp 125-141

Coenzyme Q10 provides neuroprotection in iron-induced apoptosis in dopaminergic neurons

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The exact molecular mechanism of progressive loss of neuromelanin containing nigrostriatal dopaminergic neurons in Parkinson's disease (PD) remains unknown, yet evidence suggests that iron might play an important role in PD pathology. In this study we have determined the neuroprotective role of coenzyme Q10 (CoQ10) in iron-induced apoptosis in cultured human dopaminergic (SK-N-SH) neurons, in metallothionein gene-manipulated mice, and in α-synuclein knockout (α-synko) mice with a primary objective to assess a possible therapeutic and anti-inflammatory potential for CoQ10 in PD. Iron-induced mitochondrial damage and apoptosis were characterized by reactive oxygen species production, increased metallothionein and glutathione synthesis, caspase-3 activation, NF-κB induction, and decreased Bcl-2 expression, without any significant change in Bax expression. Lower concentrations of FeSO4 (1–10 μM) induced perinuclear aggregation of mitochondria, whereas higher concentrations (100–250 μM) induced CoQ10 depletion, plasma membrane perforations, mitochondrial damage, and nuclear DNA condensation and fragmentation. FeSO4-induced deleterious changes were attenuated by pretreatment with CoQ10 and by deferoxamine, a potent iron chelator, in SK-N-SH cells. 1-Methyl, 4-phenyl, 1,2,3,6-tetrahydropyridine (MPTP)-induced striatal release of free iron, and NF-κB expression were significantly increased; whereas ferritin and melanin synthesis were significnatly reduced in the substantia nigra pars compacta (SN pc) of MTdko mice as compared with controlwt mice, MTtrans mice, and α-synko mice. CoQ10 treatment inhibited MPTP-induced NF-κB induction in all of the genotypes. These data suggest that glutathione and metallothionein synthesis might be induced as an attempt to combat iron-induced oxidative stress, whereas exogenous administration of CoQ10 or of metallothionein induction might provide CoQ10-mediated neuroprotection in PD.