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Induction of mitochondrial oxidative stress in astrocytes by nitric oxide precedes disruption of energy metabolism
Author(s) -
Jacobson Jake,
Duchen Michael R.,
Hothersall John,
Clark John B.,
Heales Simon J. R.
Publication year - 2005
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 - 10.1111/j.1471-4159.2005.03374.x
Subject(s) - mitochondrion , oxidative phosphorylation , reactive oxygen species , oxidative stress , nitric oxide , microbiology and biotechnology , intracellular , mitochondrial ros , biochemistry , atp synthase , metabolism , biology , chemistry , enzyme , endocrinology
Abstract Inhibition of the mitochondrial electron transport chain (ETC) ultimately limits ATP production and depletes cellular ATP. However, the individual complexes of the ETC in brain mitochondria need to be inhibited by ∼ 50% before causing significant depression of ATP synthesis. Moreover, the ETC is the key site for the production of intracellular reactive oxygen species (ROS) and inhibition of one or more of the complexes of the ETC may increase the rate of mitochondrial ROS generation. We asked whether partial inhibition of the ETC, to a degree insufficient to perturb oxidative phosphorylation, might nonetheless induce ROS production. Chronic increase in mitochondrial ROS might then cause oxidative damage to the ETC sufficient to produce prolonged changes in ETC function and so compound the defect. We show that the exposure of astrocytes in culture to low concentrations of nitric oxide (NO) induces an increased rate of O 2 ·− generation that outlasts the presence of NO. No effect was seen on oxygen consumption, lactate or ATP content over the 4–6 h that the cells were exposed to NO. These data suggest that partial ETC inhibition by NO may initially cause oxidative stress rather than ATP depletion, and this may subsequently induce irreversible changes in ETC function providing the basis for a cycle of damage.