Differences in vulnerability of neurons and astrocytes to heme oxygenase-1 modulation: Implications for mitochondrial ferritin

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Abstract

Induction of the antioxidant enzyme heme oxygenase-1 (HO-1) was observed in both astrocytes and neurons in the substantia nigra of patients with Parkinson's disease (PD). In the current study, we investigated whether HO-1 behaves differently between neurons and astrocytes under the condition of neurotoxicity related to PD. The results showed a time-dependent HO-1 upregulation in primary cultured ventral mesencephalon neurons and astrocytes treated with the mitochondria complex I inhibitor 1-methyl-4-phenylpyridinium (MPP(+)) or recombinant α-synuclein. However, HO-1 upregulation appeared much later in neurons than in astrocytes. The HO-1 inhibitor zinc protoporphyrin (ZnPP) aggravated MPP(+)- or α-synuclein-induced oxidative damage in both astrocytes and neurons, indicating that this HO-1 response was cytoprotective. For neurons, the HO-1 activator cobalt protoporphyrin IX (CoPPIX) exerted protective effects against MPP(+) or α-synuclein during moderate HO-1 upregulation, but it aggravated damage at the peak of the HO-1 response. For astrocytes, CoPPIXalways showed protective effects. Higher basal and CoPPIX-induced mitochondrial ferritin (MtFt) levels were detected in astrocytes. Lentivirus-mediated MtFt overexpression rescued the neuronal damage induced by CoPPIX, indicating that large MtFt buffering capacity contributes to pronounced HO-1 tolerance in astrocytes. Such findings suggest that astrocyte-targeted HO-1 interventions and MtFt modulations have potential as novel pharmacological strategies in PD.

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