Document Detail


Glutathione redox status in mitochondria and cytoplasm differentially and sequentially activates apoptosis cascade in dopamine-melanin-treated SH-SY5Y cells.
MedLine Citation:
PMID:  19737600     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
Neuromelanin (NM)-containing dopaminergic neurons in the substantia nigra are selectively vulnerable in Parkinson's disease (PD), suggesting the involvement of NM in the pathogenesis. NM is composed of protein, lipid, trace metals and melanin component, a mixture of eumelanin produced from dopamine (DA)-quinone and pheomelanin containing 5-S-cyteinyl-DA-quinone. We reported that NM induces mitochondria-mediated apoptosis in human dopaminergic SH-SY5Y cells, which was suppressed completely by Protease K-treatment, suggesting the essential requirement for the protein component. In this paper, the role of the melanin component in NM-dependent apoptosis was studied using SH-SY5Y cells and synthesized DA-melanin (DAM) and L-cysteinyl-DAM (Cys-DAM). DAM oxidatively decreased glutathione (GSH) and sulfhydryl (SH) content in mitochondria, whereas NM increased GSH by de-S-glutathionylation of complex I. DAM induced mitochondrial permeability transition (mPT), leading to membrane potential collapse and cytochrome c release, whereas Cys-DAM did not. However, the cytotoxicity of DAM itself was rather mild and thiol-targeting reducing reagents, including GSH, dithiothreitol and N-acetyl-cysteine, increased apoptosis significantly. The reducing SH reagents activated caspase 3 and induced apoptosis, but did not affect mPT. On the other hand, NM itself activated mitochondria-initiated apoptotic cascade, which GSH suppressed completely. The results indicate that DAM induces apoptosis through the sequential activation by oxidation of SH status in mitochondria and reduction in cytoplasm, in contrast to the case with NM. The regulation of apoptotic processing by SH redox state is discussed in relation to degeneration of nigra-striatal DA neurons in aging and PD, where oxidative stress is increased with impaired antioxidant capacity.
Authors:
Makoto Naoi; Hong Yi; Wakako Maruyama; Keiko Inaba; Masayo Shamoto-Nagai; Yukihiro Akao; Manfred Gerlach; Peter Riederer
Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't     Date:  2009-09-06
Journal Detail:
Title:  Neuroscience letters     Volume:  465     ISSN:  1872-7972     ISO Abbreviation:  Neurosci. Lett.     Publication Date:  2009 Nov 
Date Detail:
Created Date:  2009-09-30     Completed Date:  2010-01-14     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  7600130     Medline TA:  Neurosci Lett     Country:  Ireland    
Other Details:
Languages:  eng     Pagination:  118-22     Citation Subset:  IM    
Affiliation:
Department of Neurosciences, Gifu International Institute of Biotechnology, 1-1 Nakafudogaoka, Kakamigahara, Gifu 504-0838, Japan. mnaoi@giib.or.jp
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MeSH Terms
Descriptor/Qualifier:
Apoptosis / physiology*
Caspase 3 / metabolism
Cell Line, Tumor
Cytochromes c / metabolism
Cytoplasm / metabolism*
Dopamine / metabolism*
Glutathione / metabolism*
Humans
Melanins / metabolism*
Membrane Potential, Mitochondrial / physiology
Mitochondria / metabolism*
Oxidation-Reduction
Signal Transduction / physiology
Sulfhydryl Compounds / metabolism
Time Factors
Chemical
Reg. No./Substance:
0/Melanins; 0/Sulfhydryl Compounds; 70-18-8/Glutathione; 9007-43-6/Cytochromes c; EC 3.4.22.-/CASP3 protein, human; EC 3.4.22.-/Caspase 3

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