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Modulation of mitochondrial membrane potential and reactive oxygen species production by copper in astrocytes
Author(s) -
Gyulkhandanyan Armen V.,
Feeney Chris J.,
Pennefather Peter S.
Publication year - 2003
Publication title -
journal of neurochemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.75
H-Index - 229
eISSN - 1471-4159
pISSN - 0022-3042
DOI - 10.1046/j.1471-4159.2003.02029.x
Subject(s) - rotenone , menadione , reactive oxygen species , oxidative stress , mitochondrial permeability transition pore , chemistry , copper toxicity , mitochondrion , biochemistry , copper , respiratory chain , biophysics , superoxide , biology , programmed cell death , apoptosis , organic chemistry , enzyme
In monolayers of cultured rat astrocytes a number of agents that induce oxidative stress act synergistically with exposure to copper leading to rapid depolarization of the mitochondrial membrane potential (Ψ m ) and increased reactive oxygen species (ROS) production. Copper sensitized astrocytes to the action of menadione, an intracellular generator of superoxide anion radical, exogenous hydrogen peroxide (H 2 O 2 ) and rotenone, an inhibitor of mitochondrial electron transport chain complex I. However, significant differences were observed in the ability to modulate the copper‐enhanced oxidative stress depending on which stressor was used. The inhibitor of mitochondrial permeability transition cyclosporin A attenuated the effect of copper and rotenone, but had no protective action in the case of H 2 O 2 /copper and menadione/copper combinations. The H 2 O 2 scavenger pyruvate was effective at protecting mitochondria against damage associated with the combined exposure to H 2 O 2 /copper and menadione/copper but not to the rotenone/copper combination. The antioxidant Trolox was ineffective at protecting against any of these actions and indeed had a damaging effect when combined with copper. The membrane‐permeable copper chelator neocuproine combined with sensitizing concentrations of menadione caused a decrease in Ψ m , mimicking the action of copper. Penicillamine, a membrane‐impermeable copper chelator, was effective at reducing copper sensitization. Endogenous copper, mobilized during periods of oxidative stress, may play a role in the pathophysiology of brain injury. Our results suggest that this might be particularly dangerous in dysfunctional conditions in which the mitochondrial electron transport chain is compromised.