Autophagy protects against aminochrome-induced cell death in substantia nigra-derived cell line.

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.

• Authors: Irmgard Paris, Patricia Muñoz, Sandro Huenchuguala, Eduardo Couve, Laurie H Sanders, John Timothy Greenamyre, Pablo Caviedes, Juan Segura-Aguilar
• Journal: Toxicological sciences : an official journal of the Society of Toxicology (Toxicol Sci) Vol. 121 Issue 2 Pg. 376-88 (Jun 2011) ISSN: 1096-0929 [Electronic] United States
• PMID: 21427056 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• DNA, Mitochondrial
• Indolequinones
• Melanins
• neuromelanin
• aminochrome 1
• Vinblastine
• Cytochromes c
• NAD(P)H Dehydrogenase (Quinone)
• Casp3 protein, rat
• Caspase 3
• Sirolimus

Topics

• Animals
• Autophagy (drug effects)
• Caspase 3 (metabolism)
• Cell Death (drug effects)
• Cell Line
• Cytochromes c (metabolism)
• DNA, Mitochondrial (metabolism)
• Indolequinones (toxicity)
• Melanins (metabolism)
• Membrane Potential, Mitochondrial
• Microscopy, Electron, Transmission
• Mitochondria (metabolism)
• NAD(P)H Dehydrogenase (Quinone) (antagonists & inhibitors)
• Nerve Degeneration (metabolism)
• Rats
• Sirolimus (pharmacology)
• Substantia Nigra (cytology, drug effects, metabolism)
• Vinblastine (pharmacology)