Reactive oxygen species induced by proteasome inhibition in neuronal cells mediate mitochondrial dysfunction and a caspase-independent cell death |
| |
Authors: | Luena Papa Evan Gomes Patricia Rockwell |
| |
Institution: | (1) Department of Biological Sciences, Hunter College of The City University of New York, 695 Park Ave, New York, NY 10021, USA |
| |
Abstract: | While increasing evidence shows that proteasome inhibition triggers oxidative damage, mitochondrial dysfunction and death
in neuronal cells, the regulatory relationship among these events is unclear. Using mouse neuronal cells we show that the
cytotoxicity induced by mild (0.25 μM) and potent (5.0 μM) doses of the proteasome inhibitor, N-Benzyloxycarbonyl-Ile-Glu (O-t-butyl)-Ala-leucinal, (PSI) involved a dose-dependent increase in caspase activation, overproduction of reactive oxygen species
(ROS) and a mitochondrial dysfunction manifested by the translocation of the proapoptotic protein, Bax, from the cytoplasm
to the mitochondria, membrane depolarization and the release of cytochrome c and the apoptosis inducing factor (AIF) from mitochondria to the cytoplasm and nucleus, respectively. Whereas caspase or
Bax inhibition failed to prevent mitochondrial membrane depolarization and neuronal cell death, pretreatments with the antioxidant
N-acetyl-l-cysteine (NAC) or overexpression of the antiapoptotic protein Bcl-xL abrogated these events in cells exposed to mild levels
of PSI. These findings implicated ROS as a mediator of PSI-induced cytotoxicity. However, depletions in glutathione and Bcl-xL
with potent proteasome inhibition exacerbated this response whereupon survival required the cooperative protection of NAC
with Bcl-xL overexpression. Collectively, ROS induced by proteasome inhibition mediates a mitochondrial dysfunction in neuronal
cells that culminates in death through caspase- and Bax-independent mechanisms.
Electronic Supplementary Material The online version of this article (doi:) contains supplementary material, which is available to authorized users. |
| |
Keywords: | Caspase activation Mitochondrial dysfunction Reactive oxygen species Proteasome inhibition Neuronal cell death |
本文献已被 PubMed SpringerLink 等数据库收录! |
|