Proteasome inhibition in oxidative stress neurotoxicity: implications for heat shock proteins.
Recent studies have demonstrated that inhibition of the proteasome, an enzyme responsible for the majority of intracellular proteolysis, may contribute to the toxicity associated with oxidative stress. In the present study we demonstrate that exposure to oxidative injury (paraquat, H(2)O(2), FeSO(4)) induces a rapid increase in reactive oxygen species (ROS), loss of mitochondrial membrane potential, inhibition of proteasome activity, and induction of cell death in neural SH-SY5Y cells. Application of proteasome inhibitors (MG115, epoxomycin) mimicked the effects of oxidative stressors on mitochondrial membrane potential and cell viability, and increased vulnerability to oxidative injury. Neural SH-SY5Y cells stably transfected with human HDJ-1, a member of the heat shock protein family, were more resistant to the cytotoxicity associated with oxidative stressors. Cells expressing increased levels of HDJ-1 displayed similar degrees of ROS formation following oxidative stressors, but demonstrated a greater preservation of mitochondrial function and proteasomal activity following oxidative injury. Cells transfected with HDJ-1 were also more resistant to the toxicity associated with proteasome inhibitor application. These data support a possible role for proteasome inhibition in the toxicity of oxidative stress, and suggest heat shock proteins may confer resistance to oxidative stress, by preserving proteasome function and attenuating the toxicity of proteasome inhibition.
Ding
Q
Q
Department of Anatomy and Neurobiology, University of Kentucky, Lexington, Kentucky, USA.
Keller
J N
JN
D000818:Animals; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D003546:Cysteine Endopeptidases / Q000378:metabolism*; D050956:HSP40 Heat-Shock Proteins; D006360:Heat-Shock Proteins / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D006861:Hydrogen Peroxide / Q000633:toxicity; D007425:Intracellular Membranes / Q000502:physiology; D007700:Kinetics; D007976:Leupeptins / Q000494:pharmacology; D008564:Membrane Potentials / Q000187:drug effects / Q000502:physiology; D008928:Mitochondria / Q000502:physiology; D009097:Multienzyme Complexes / Q000378:metabolism*; D009474:Neurons / Q000166:cytology / Q000187:drug effects / Q000502:physiology*; D009498:Neurotoxins / Q000633:toxicity; D009842:Oligopeptides / Q000494:pharmacology; D018384:Oxidative Stress / Q000187:drug effects / Q000502:physiology*; D010269:Paraquat / Q000633:toxicity; D011480:Protease Inhibitors / Q000494:pharmacology*; D046988:Proteasome Endopeptidase Complex; D017382:Reactive Oxygen Species / Q000378:metabolism; D011994:Recombinant Proteins / Q000378:metabolism; D014162:Transfection
D050956:HSP40 Heat-Shock Proteins; D006360:Heat-Shock Proteins; D007976:Leupeptins; D009097:Multienzyme Complexes; D009498:Neurotoxins; D009842:Oligopeptides; D011480:Protease Inhibitors; D017382:Reactive Oxygen Species; D011994:Recombinant Proteins; C089486:carbobenzoxy-leucyl-leucyl-norvalinal; D006861:Hydrogen Peroxide; D003546:Cysteine Endopeptidases; D046988:Proteasome Endopeptidase Complex; D010269:Paraquat; C078846:epoxomicin