Document Detail


Metallothionein isoform 2A expression is inducible and protects against ROS-mediated cell death in rotenone-treated HeLa cells.
MedLine Citation:
PMID:  16402917     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
The role of MT (metallothionein) gene expression was investigated in rotenone-treated HeLa cells to induce a deficiency of NADH:ubiquinone oxidoreductase (complex I). Complex I deficiency leads to a diversity of cellular consequences, including production of ROS (reactive oxygen species) and apoptosis. HeLa cells were titrated with rotenone, resulting in dose-dependent decrease in complex I activity and elevated ROS production at activities lower than 33%. Expression of MT2A (MT isoform 2A), but not MT1A or MT1B RNA, was significantly inducible by rotenone (up to 7-fold), t-BHP (t-butyl hydroperoxide; 5-fold) and CdCl2 (50-fold), but not ZnCl2. Myxothiazol treatment did not elevate either ROS or MT2A levels, which supports a ROS-related mechanism for rotenone-induced MT2A expression. To evaluate the role of MT2A expression, MT2A and MT1B were overexpressed in HeLa cells and treated with rotenone. Compared with control and MT1B-overexpressing cells, ROS production was significantly lower and cell viability higher in MT2A-overexpressing HeLa cells when ROS production was enhanced by treatment with t-BHP. Mitochondrial membrane potential was noticeably less reduced in both MT-overexpressing cell lines. MT2A overexpression in rotenone-treated cells also significantly reduced or delayed apoptosis induction, as measured by caspase 3/7 activity and cytosolic nucleosome enrichment. We conclude that MT2A offers significant protection against the main death-causing consequences of rotenone-induced complex I deficiency in HeLa cells. Our results are in support of the protective role against oxidative stress ascribed to MTs and provide evidence that MT2A expression may be a beneficial downstream adaptive response in complex I-deficient cells.
Authors:
Fimmie Reinecke; Oksana Levanets; Yolanda Olivier; Roan Louw; Boitumelo Semete; Anne Grobler; Juan Hidalgo; Jan Smeitink; Antonel Olckers; Francois H Van der Westhuizen
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't    
Journal Detail:
Title:  The Biochemical journal     Volume:  395     ISSN:  1470-8728     ISO Abbreviation:  Biochem. J.     Publication Date:  2006 Apr 
Date Detail:
Created Date:  2006-03-27     Completed Date:  2006-04-18     Revised Date:  2013-06-07    
Medline Journal Info:
Nlm Unique ID:  2984726R     Medline TA:  Biochem J     Country:  England    
Other Details:
Languages:  eng     Pagination:  405-15     Citation Subset:  IM    
Affiliation:
Division of Biochemistry, School for Chemistry and Biochemistry, North-West University, Potchefstroom 2531, South Africa.
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MeSH Terms
Descriptor/Qualifier:
Adenosine Triphosphate / analysis
Apoptosis / drug effects
Cell Death / drug effects
Cell Survival / drug effects
Cells, Cultured
Electron Transport Complex I / drug effects
Electron Transport Complex III / drug effects
HeLa Cells
Humans
Membrane Potentials / drug effects
Metallothionein / genetics,  metabolism*
Mitochondria / metabolism
Protein Isoforms / genetics,  metabolism
RNA, Messenger / genetics,  metabolism
Reactive Oxygen Species / metabolism*
Recombinant Proteins / metabolism
Rotenone / pharmacology*
Up-Regulation / drug effects*
tert-Butylhydroperoxide / pharmacology
Chemical
Reg. No./Substance:
0/Protein Isoforms; 0/RNA, Messenger; 0/Reactive Oxygen Species; 0/Recombinant Proteins; 56-65-5/Adenosine Triphosphate; 75-91-2/tert-Butylhydroperoxide; 83-79-4/Rotenone; 9038-94-2/Metallothionein; EC 1.10.2.2/Electron Transport Complex III; EC 1.6.5.3/Electron Transport Complex I
Comments/Corrections

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