TY - JOUR
T1 - Distinct mechanisms of neurodegeneration induced by chronic complex I inhibition in dopaminergic and non-dopaminergic cells
AU - Kweon, Gi Ryang
AU - Marks, Jeremy D.
AU - Krencik, Robert
AU - Leung, Eric H.
AU - Schumacker, Paul T.
AU - Hyland, Keith
AU - Un, Jung Kang
PY - 2004/12/10
Y1 - 2004/12/10
N2 - 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 MN9B cells: rotenone oxidatively modified proteins more in MN9X cells than in MN9D cells and anti-oxidants 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 MN9B cells more than in MN9X cells. Supplementation of cellular energy with a ketone body, D-β-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, MN9B 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.
AB - 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 MN9B cells: rotenone oxidatively modified proteins more in MN9X cells than in MN9D cells and anti-oxidants 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 MN9B cells more than in MN9X cells. Supplementation of cellular energy with a ketone body, D-β-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, MN9B 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.
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U2 - 10.1074/jbc.M407336200
DO - 10.1074/jbc.M407336200
M3 - Article
C2 - 15469939
AN - SCOPUS:10644270649
SN - 0021-9258
VL - 279
SP - 51783
EP - 51792
JO - Journal of Biological Chemistry
JF - Journal of Biological Chemistry
IS - 50
ER -