Autophagy protects against aminochrome-induced cell death in substantia nigra-derived cell line.
Toxicol Sci
; 121(2): 376-88, 2011 Jun.
Article
em En
| MEDLINE
| ID: mdl-21427056
ABSTRACT
Aminochrome, the precursor of neuromelanin, has been proposed to be involved in the neurodegeneration neuromelanin-containing dopaminergic neurons in Parkinson's disease. We aimed to study the mechanism of aminochrome-dependent cell death in a cell line derived from rat substantia nigra. We found that aminochrome (50µM), in the presence of NAD(P)H-quinone oxidoreductase, EC 1.6.99.2 (DT)-diaphorase inhibitor dicoumarol (DIC) (100µM), induces significant cell death (62 ± 3%; p < 0.01), increase in caspase-3 activation (p < 0.001), release of cytochrome C, disruption of mitochondrial membrane potential (p < 0.01), damage of mitochondrial DNA, damage of mitochondria determined with transmission electron microscopy, a dramatic morphological change characterized as cell shrinkage, and significant increase in number of autophagic vacuoles. To determine the role of autophagy on aminochrome-induced cell death, we incubated the cells in the presence of vinblastine and rapamycin. Interestingly, 10µM vinblastine induces a 5.9-fold (p < 0.001) and twofold (p < 0.01) significant increase in cell death when the cells were incubated with 30µM aminochrome in the absence and presence of DIC, respectively, whereas 10µM rapamycin preincubated 24 h before addition of 50µM aminochrome in the absence and the presence of 100µM DIC induces a significant decrease (p < 0.001) in cell death. In conclusion, autophagy seems to be an important protective mechanism against two different aminochrome-induced cell deaths that initially showed apoptotic features. The cell death induced by aminochrome when DT-diaphorase is inhibited requires activation of mitochondrial pathway, whereas the cell death induced by aminochrome alone requires inhibition of autophagy-dependent degrading of damaged organelles and recycling through lysosomes.
Texto completo:
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Base de dados:
MEDLINE
Assunto principal:
Autofagia
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Substância Negra
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Morte Celular
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Indolquinonas
Limite:
Animals
Idioma:
En
Ano de publicação:
2011
Tipo de documento:
Article