Reactive oxygen species induced by proteasome inhibition in neuronal cells mediate mitochondrial dysfunction and a caspase-independent cell death
- 6 April 2007
- journal article
- Published by Springer Science and Business Media LLC in Apoptosis
- Vol. 12 (8), 1389-1405
- https://doi.org/10.1007/s10495-007-0069-5
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.Keywords
This publication has 59 references indexed in Scilit:
- Oxidative stress and neurodegeneration: where are we now?Journal of Neurochemistry, 2006
- Proteasome inhibition induces reversible impairments in protein synthesisThe FASEB Journal, 2006
- Curcumin protects PC12 cells against 1-methyl-4-phenylpyridinium ion-induced apoptosis by bcl-2-mitochondria-ROS-iNOS pathwayApoptosis, 2006
- Apoptosis and the conformational change of Bax induced by proteasomal inhibition of PC12 cells are inhibited by bcl-xL and bcl-2Apoptosis, 2005
- Application of proteasomal inhibitors to mouse sympathetic neurons activates the intrinsic apoptotic pathwayJournal of Neurochemistry, 2004
- Systemic exposure to proteasome inhibitors causes a progressive model of Parkinson's diseaseAnnals of Neurology, 2004
- Regulation of apoptosis proteins in cancer cells by ubiquitinOncogene, 2004
- The hierarchical relationship between MAPK signaling and ROS generation in human leukemia cells undergoing apoptosis in response to the proteasome inhibitor BortezomibExperimental Cell Research, 2004
- Alternating metabolic pathways in NGF-deprived sympathetic neurons affect caspase-independent deathThe Journal of cell biology, 2003
- Proapoptotic BAX and BAK: A Requisite Gateway to Mitochondrial Dysfunction and DeathScience, 2001