Document Detail


Mitochondrial aconitase knockdown attenuates paraquat-induced dopaminergic cell death via decreased cellular metabolism and release of iron and H₂O₂.
MedLine Citation:
PMID:  21517855     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
Mitochondrial oxidative stress is a contributing factor in the etiology of numerous neuronal disorders. However, the precise mechanism(s) by which mitochondrial reactive oxygen species modify cellular targets to induce neurotoxicity remains unknown. In this study, we determined the role of mitochondrial aconitase (m-aconitase) in neurotoxicity by decreasing its expression. Incubation of the rat dopaminergic cell line, N27, with paraquat (PQ(2+) ) resulted in aconitase inactivation, increased hydrogen peroxide (H(2) O(2) ) and increased ferrous iron (Fe(2+) ) at times preceding cell death. To confirm the role of m-aconitase in dopaminergic cell death, we knocked down m-aconitase expression via RNA interference. Incubation of m-aconitase knockdown N27 cells with PQ(2+) resulted in decreased H(2) O(2) production, Fe(2+) accumulation, and cell death compared with cells expressing basal levels of m-aconitase. To determine the metabolic role of m-aconitase in mediating neuroprotection, we conducted a complete bioenergetic profile. m-Aconitase knockdown N27 cells showed a global decrease in metabolism (glycolysis and oxygen consumption rates) which blocked PQ(2+) -induced H(+) leak and respiratory capacity deficiency. These findings suggest that dopaminergic cells are protected from death by decreasing release of H(2) O(2) and Fe(2+) in addition to decreased cellular metabolism.
Authors:
David Cantu; Ruth E Fulton; Derek A Drechsel; Manisha Patel
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural     Date:  2011-05-19
Journal Detail:
Title:  Journal of neurochemistry     Volume:  118     ISSN:  1471-4159     ISO Abbreviation:  J. Neurochem.     Publication Date:  2011 Jul 
Date Detail:
Created Date:  2011-06-10     Completed Date:  2011-08-12     Revised Date:  2014-09-20    
Medline Journal Info:
Nlm Unique ID:  2985190R     Medline TA:  J Neurochem     Country:  England    
Other Details:
Languages:  eng     Pagination:  79-92     Citation Subset:  IM    
Copyright Information:
Published 2011. This article is a US Government work and is in the public domain in the USA. Journal of Neurochemistry © 2011 International Society for Neurochemistry.
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MeSH Terms
Descriptor/Qualifier:
Aconitate Hydratase / deficiency,  genetics,  metabolism*
Analysis of Variance
Animals
Antimycin A / pharmacology
Carbonyl Cyanide p-Trifluoromethoxyphenylhydrazone / pharmacology
Cell Death / drug effects
Cell Line, Transformed
Dopamine / metabolism*
Fumarate Hydratase / metabolism
Gene Expression Regulation / drug effects
Herbicides / toxicity
Hydrogen Peroxide / metabolism*
Ionophores / pharmacology
Iron / metabolism*
L-Lactate Dehydrogenase / metabolism
Mitochondria / drug effects,  metabolism*
Oxygen Consumption / drug effects,  physiology
Paraquat / toxicity
Protons
RNA, Messenger / metabolism
RNA, Small Interfering / genetics,  metabolism
Rats
Time Factors
Transfection / methods
Grant Support
ID/Acronym/Agency:
NS039587/NS/NINDS NIH HHS; NS039587-S1/NS/NINDS NIH HHS; NS045748/NS/NINDS NIH HHS; R01 NS039587/NS/NINDS NIH HHS; R01 NS039587-11/NS/NINDS NIH HHS; R01 NS045748/NS/NINDS NIH HHS; R01 NS045748-07/NS/NINDS NIH HHS; R01 NS045748-08/NS/NINDS NIH HHS
Chemical
Reg. No./Substance:
0/Herbicides; 0/Ionophores; 0/Protons; 0/RNA, Messenger; 0/RNA, Small Interfering; 370-86-5/Carbonyl Cyanide p-Trifluoromethoxyphenylhydrazone; 642-15-9/Antimycin A; BBX060AN9V/Hydrogen Peroxide; E1UOL152H7/Iron; EC 1.1.1.27/L-Lactate Dehydrogenase; EC 4.2.1.2/Fumarate Hydratase; EC 4.2.1.3/Aconitate Hydratase; PLG39H7695/Paraquat; VTD58H1Z2X/Dopamine
Comments/Corrections

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