Document Detail


Distinct mechanisms of neurodegeneration induced by chronic complex I inhibition in dopaminergic and non-dopaminergic cells.
MedLine Citation:
PMID:  15469939     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
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.
Authors:
Gi-Ryang Kweon; Jeremy D Marks; Robert Krencik; Eric H Leung; Paul T Schumacker; Keith Hyland; Un Jung Kang
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't; Research Support, U.S. Gov't, P.H.S.     Date:  2004-10-06
Journal Detail:
Title:  The Journal of biological chemistry     Volume:  279     ISSN:  0021-9258     ISO Abbreviation:  J. Biol. Chem.     Publication Date:  2004 Dec 
Date Detail:
Created Date:  2004-12-06     Completed Date:  2005-02-01     Revised Date:  2014-09-20    
Medline Journal Info:
Nlm Unique ID:  2985121R     Medline TA:  J Biol Chem     Country:  United States    
Other Details:
Languages:  eng     Pagination:  51783-92     Citation Subset:  IM    
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MeSH Terms
Descriptor/Qualifier:
Animals
Antioxidants / pharmacology
Cell Differentiation
Cell Line
Dopamine / metabolism*
Electron Transport Complex I / antagonists & inhibitors*
Glycolysis
Mice
Models, Neurological
Nerve Degeneration / chemically induced,  metabolism*,  pathology
Neurons / drug effects,  metabolism,  pathology
Oxidative Phosphorylation
Oxidative Stress
Rotenone / toxicity
Grant Support
ID/Acronym/Agency:
HL66315/HL/NHLBI NIH HHS; NS32080/NS/NINDS NIH HHS; NS38547/NS/NINDS NIH HHS; R01 NS038547/NS/NINDS NIH HHS; R01 NS038547-01A1/NS/NINDS NIH HHS; R01 NS038547-02/NS/NINDS NIH HHS; R01 NS038547-03/NS/NINDS NIH HHS; R01 NS038547-04/NS/NINDS NIH HHS; R01 NS038547-05/NS/NINDS NIH HHS; R01 NS43286/NS/NINDS NIH HHS; T32 GM07281/GM/NIGMS NIH HHS
Chemical
Reg. No./Substance:
0/Antioxidants; 03L9OT429T/Rotenone; EC 1.6.5.3/Electron Transport Complex I; VTD58H1Z2X/Dopamine

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