The role of microglial mtDNA damage in age-dependent prolonged LPS-induced sickness behavior.
Microglia are the main cellular source of oxidation products and inflammatory molecules in the brain during aging. The accumulation of mitochondrial DNA (mtDNA) oxidative damage in microglia during aging results in the increased production of reactive oxygen species (ROS). The increased intracellular ROS, in turn, activates a redox-sensitive nuclear factor-κB (NF-κB) to provoke excessive neuroinflammation, resulting in memory deficits and the prolonged behavioral consequence of infection. Besides its role in regulating the gene copy number, mitochondrial transcription factor A (TFAM) is closely associated with the stabilization of mtDNA structures. Lipopolysaccharide (LPS) induces the generation of ROS from the actively respirating mitochondria as well as NADPH oxidase, and leads to the subsequent activation of the NF-κB-dependent inflammatory pathway in aging microglia. The overexpression of human TFAM improves the age-dependent prolonged LPS-induced sickness behaviors by ameliorating the mtDNA damage and reducing the resultant redox-regulated inflammatory responses. Therefore, 'microglia-aging' plays important roles in the age-dependent enhanced behavioral consequences of infection.
Department of Aging Science and Pharmacology, Faculty of Dental Sciences, Kyushu University, Fukuoka 812-8582, Japan. nakan@dent.kyushu-u.ac.jp
Hiroshi
H
Nakanishi
Yoshinori
Y
Hayashi
Zhou
Z
Wu
D000375:Aging / Q000187:drug effects*; D000818:Animals; D016207:Cytokines / Q000378:metabolism; D004272:DNA, Mitochondrial / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000378:metabolism; D018507:Gene Expression Regulation, Developmental / Q000187:drug effects; D006801:Humans; D055809:Illness Behavior / Q000187:drug effects*; D008070:Lipopolysaccharides / Q000494:pharmacology*; D051379:Mice; D017628:Microglia / Q000187:drug effects / Q000502:physiology; D024101:Mitochondrial Proteins / Q000378:metabolism; D017382:Reactive Oxygen Species; D014157:Transcription Factors / Q000378:metabolism
D016207:Cytokines; D004272:DNA, Mitochondrial; D004268:DNA-Binding Proteins; D008070:Lipopolysaccharides; D024101:Mitochondrial Proteins; D017382:Reactive Oxygen Species; C499631:TFAM protein, human; D014157:Transcription Factors