Metabolic impairment induces oxidative stress, compromises inflammatory responses, and inactivates a key mitochondrial enzyme in microglia

Citation
Lch. Park et al., Metabolic impairment induces oxidative stress, compromises inflammatory responses, and inactivates a key mitochondrial enzyme in microglia, J NEUROCHEM, 72(5), 1999, pp. 1948-1958
Citations number
77
Categorie Soggetti
Neurosciences & Behavoir
Journal title
JOURNAL OF NEUROCHEMISTRY
ISSN journal
00223042 → ACNP
Volume
72
Issue
5
Year of publication
1999
Pages
1948 - 1958
Database
ISI
SICI code
0022-3042(199905)72:5<1948:MIIOSC>2.0.ZU;2-W
Abstract
Microglial activation, oxidative stress, and dysfunctions in mitochondria, including the reduction of cytochrome oxidase activity, have been implicate d in neurodegeneration. The current experiments tested the effects of reduc ing cytochrome oxidase activity on the ability of microglia to respond to i nflammatory insults. Inhibition of cytochrome oxidase by azide reduced oxyg en consumption and increased reactive oxygen species (ROS) production but d id not affect cell viability. Azide also attenuated microglial activation, as measured by nitric oxide (NO.) production in response to lipopolysacchar ide (LPS). It is surprising that the inhibition of cytochrome oxidase also diminished the activity of the alpha-ketoglutarate dehydrogenase complex (K GDHC), a Krebs cycle enzyme. This reduction was exaggerated when the azide- treated microglia were also treated with LPS. The combination of the azide- stimulated ROS and LPS-induced NO. would likely cause peroxynitrite formati on in microglia, Thus, the possibility that KGDHC was inactivated by peroxy nitrite was tested. Peroxynitrite inhibited the activity of isolated KGDHC, nitrated tyrosine residues of all three KGDHC subunits, and reduced immuno reactivity to antibodies against two KGDHC components. Thus, our data sugge st that inhibition of the mitochondrial respiratory chain diminishes aerobi c energy metabolism, interferes with microglial inflammatory responses, and compromises mitochondrial function, including KGDHC activity, which is vul nerable to NO. and peroxynitrite that result from microglial activation. Th us, activation of metabolically compromised microglia can further diminish their oxidative capacity, creating a deleterious spiral that may contribute to neurodegeneration.