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

被引:112
作者
Park, LCH
Zhang, H
Sheu, KFR
Calingasan, NY
Kristal, BS
Lindsay, JG
Gibson, GE
机构
[1] Cornell Univ, Coll Med, Burke Med Res Inst, Dept Neurol & Neurosci, White Plains, NY 10605 USA
[2] Cornell Univ, Coll Med, Burke Med Res Inst, Dept Biochem, White Plains, NY 10605 USA
[3] Univ Glasgow, Dept Biochem, Glasgow G12 8QQ, Lanark, Scotland
关键词
alpha-ketoglutarate dehydrogenase complex; mitochondrial complex IV; reactive oxygen species; nitric oxide; peroxynitrite; azide; metabolic impairment;
D O I
10.1046/j.1471-4159.1999.0721948.x
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
Microglial activation, oxidative stress, and dysfunctions in mitochondria, including the reduction of cytochrome oxidase activity, have been implicated in neurodegeneration. The current experiments tested the effects of reducing cytochrome oxidase activity on the ability of microglia to respond to inflammatory insults. Inhibition of cytochrome oxidase by azide reduced oxygen consumption and increased reactive oxygen species (ROS) production but did not affect cell viability. Azide also attenuated microglial activation, as measured by nitric oxide (NO.) production in response to lipopolysaccharide (LPS). It is surprising that the inhibition of cytochrome oxidase also diminished the activity of the alpha-ketoglutarate dehydrogenase complex (KGDHC), 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 formation in microglia, Thus, the possibility that KGDHC was inactivated by peroxynitrite was tested. Peroxynitrite inhibited the activity of isolated KGDHC, nitrated tyrosine residues of all three KGDHC subunits, and reduced immunoreactivity to antibodies against two KGDHC components. Thus, our data suggest that inhibition of the mitochondrial respiratory chain diminishes aerobic energy metabolism, interferes with microglial inflammatory responses, and compromises mitochondrial function, including KGDHC activity, which is vulnerable to NO. and peroxynitrite that result from microglial activation. Thus, activation of metabolically compromised microglia can further diminish their oxidative capacity, creating a deleterious spiral that may contribute to neurodegeneration.
引用
收藏
页码:1948 / 1958
页数:11
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