title: Reverse of age-dependent memory impairment and mitochondrial DNA damage in microglia by an overexpression of human mitochondrial transcription factor a in mice.
abstract: Mitochondrial DNA (mtDNA) is highly susceptible to injury induced by reactive oxygen species (ROS). During aging, mutations of mtDNA accumulate to induce dysfunction of the respiratory chain, resulting in the enhanced ROS production. Therefore, age-dependent memory impairment may result from oxidative stress derived from the respiratory chain. Mitochondrial transcription factor A (TFAM) is now known to have roles not only in the replication of mtDNA but also its maintenance. We herein report that an overexpression of TFAM in HeLa cells significantly inhibited rotenone-induced mitochondrial ROS generation and the subsequent NF-kappaB (nuclear factor-kappaB) nuclear translocation. Furthermore, TFAM transgenic (TG) mice exhibited a prominent amelioration of an age-dependent accumulation of lipid peroxidation products and a decline in the activities of complexes I and IV in the brain. In the aged TG mice, deficits of the motor learning memory, the working memory, and the hippocampal long-term potentiation (LTP) were also significantly improved. The expression level of interleukin-1beta (IL-1beta) and mtDNA damages, which were predominantly found in microglia, significantly decreased in the aged TG mice. The IL-1beta amount markedly increased in the brain of the TG mice after treatment with lipopolysaccharide (LPS), whereas its mean amount was significantly lower than that of the LPS-treated aged wild-type mice. At the same time, an increased mtDNA damage in microglia and an impaired hippocampal LTP were also observed in the LPS-treated aged TG mice. Together, an overexpression of TFAM is therefore considered to ameliorate age-dependent impairment of the brain functions through the prevention of oxidative stress and mitochondrial dysfunctions in microglia.
authors: Laboratory of Oral Aging Science, Faculty of Dental Sciences, Kyushu University, Fukuoka 812-8582, Japan.
authors: Yoshinori
authors: Y
authors: Hayashi
authors: Masayoshi
authors: M
authors: Yoshida
authors: Mayumi
authors: M
authors: Yamato
authors: Tomomi
authors: T
authors: Ide
authors: Zhou
authors: Z
authors: Wu
authors: Mayumi
authors: M
authors: Ochi-Shindou
authors: Tomotake
authors: T
authors: Kanki
authors: Dongchon
authors: D
authors: Kang
authors: Kenji
authors: K
authors: Sunagawa
authors: Hiroyuki
authors: H
authors: Tsutsui
authors: Hiroshi
authors: H
authors: Nakanishi
mesh_terms: D000375:Aging / Q000378:metabolism / Q000523:psychology*; D000818:Animals; D001692:Biological Transport / Q000187:drug effects; D001921:Brain / Q000187:drug effects / Q000378:metabolism; D004249:DNA Damage / Q000187:drug effects*; D004272:DNA, Mitochondrial / Q000187:drug effects*; D004268:DNA-Binding Proteins / Q000235:genetics / Q000494:pharmacology*; D006367:HeLa Cells / Q000378:metabolism; D006624:Hippocampus / Q000502:physiology; D006801:Humans; D007425:Intracellular Membranes / Q000378:metabolism; D007858:Learning / Q000187:drug effects; D017774:Long-Term Potentiation / Q000187:drug effects; D008568:Memory / Q000187:drug effects; D008569:Memory Disorders / Q000523:psychology*; D051379:Mice; D008822:Mice, Transgenic / Q000235:genetics; D017628:Microglia / Q000187:drug effects*; D028361:Mitochondrial Diseases / Q000378:metabolism; D024101:Mitochondrial Proteins / Q000235:genetics / Q000494:pharmacology*; D009043:Motor Activity; D016328:NF-kappa B / Q000378:metabolism; D010084:Oxidation-Reduction / Q000187:drug effects; D018384:Oxidative Stress / Q000187:drug effects; D017382:Reactive Oxygen Species / Q000378:metabolism; D020127:Recovery of Function; D012402:Rotenone / Q000494:pharmacology; D014157:Transcription Factors / Q000235:genetics / Q000494:pharmacology*; D015854:Up-Regulation
chemical_list: D004272:DNA, Mitochondrial; D004268:DNA-Binding Proteins; D024101:Mitochondrial Proteins; D016328:NF-kappa B; D017382:Reactive Oxygen Species; D014157:Transcription Factors; C422562:mitochondrial transcription factor A; D012402:Rotenone