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Abstract
Chronic mitochondrial dysfunction, in particular of complex I, has been strongly implicated in the dopaminergic neurodegeneration in Parkinson's disease. To elucidate the mechanisms of chronic complex I disruption-induced neurodegeneration, we induced differentiation of immortalized midbrain dopaminergic (MN9D) and non-dopaminergic (MN9X) neuronal cells, to maintain them in culture without significant cell proliferation and compared their survivals following chronic exposure to nanomolar rotenone, an irreversible complex I inhibitor. Rotenone killed more dopaminergic MN9D cells than non-dopaminergic MN9X cells. Oxidative stress played an important role in rotenone-induced neurodegeneration of MN9X cells, but not MN9D cells: rotenone oxidatively modified proteins more in MN9X cells than in MN9D cells and antioxidants decreased rotenone toxicity only in MN9X cells. MN9X cells were also more sensitive to exogenous oxidants than MN9D cells. In contrast, disruption of bioenergetics played a more important role in MN9D cells: rotenone decreased mitochondrial membrane protential and ATP levels in MN9D cells more than in MN9X cells. Supplementation of cellular energy with a ketone body, D-beta-hydroxybutyrate, decreased rotenone toxicity in MN9D cells, but not in MN9X cells. MN9D cells were also more susceptible to disruption of oxidative phosphorylation or glycolysis than MN9X cells. These findings indicate that, during chronic rotenone exposure, MN9D cells die primarily through mitochondrial energy disruption, whereas MN9X cells die primarily via oxidative stress. Thus, intrinsic properties of individual cell types play important roles in determining the predominant mechanism of complex I inhibition-induced neurodegeneration.
Highlights
The pathogenesis underlying the selective degeneration of dopaminergic neurons in Parkinson’s disease (PD)1 is not fully defined, but multiple lines of evidence implicate mitochondrial dysfunction
To study the cellular mechanisms of rotenone-induced dopaminergic neuronal degeneration, we developed a novel cellular model derived from immortalized midbrain MN9D cells [15], a dopaminergic neuronal cell line that has been extensively characterized as a model of dopaminergic neurons (16 –19)
Because chronic rotenone exposure can induce oxidative stress and mitochondrial dysfunction, we have used this unique model to examine the roles of oxidative stress and bioenergetic disruption in the selective susceptibility of dopaminergic cells to rotenone neurodegeneration, processes that occur in the setting of chronic low-grade complex I inhibition
Summary
The pathogenesis underlying the selective degeneration of dopaminergic neurons in Parkinson’s disease (PD) is not fully defined, but multiple lines of evidence implicate mitochondrial dysfunction. Because chronic rotenone exposure can induce oxidative stress and mitochondrial dysfunction, we have used this unique model to examine the roles of oxidative stress and bioenergetic disruption in the selective susceptibility of dopaminergic cells to rotenone neurodegeneration, processes that occur in the setting of chronic low-grade complex I inhibition. We find that this chronic lowgrade complex I inhibition leads to cell degeneration by distinct mechanisms in dopaminergic and non-dopaminergic cells
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