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-B (nuclear factor-B) 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-1␤ (IL-1␤) and mtDNA damages, which were predominantly found in microglia, significantly decreased in the aged TG mice. The IL-1␤ 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.

Depleted Leukocyte Mitochondrial DNA Copy Number in Metabolic Syndrome

“…Similar reductions in the mtDNA copy number were reported for human immunodeficiency virus patients who were treated with nucleoside reverse transcriptase inhibitors and developed type 2 diabetes 13) . Similarly, increased mtDNA copy number via the over-expression of mitochondrial transcription factor A is proposed to serve in the defence of myocytes against cardiac failure 14) and of neurons against age-dependent memory impairment 15) . Thus, maintenance of a relatively high mtDNA copy number therefore appears to represent a physiologic process designed for tissue protection.…”

Rosiglitazone attenuates the age-related changes in astrocytosis and the deficit in LTP

“…An inhibitory effect of TNF-␣ on LTP has also been reported (Butler et al, 2004;Cumiskey et al, 2007;Tancredi et al, 1992) and it has been identified as a key mediator in the inhibitory effect of A␤ on LTP (Rowan et al, 2007). Recent evidence has indicated that when inflammatory and oxidative stress are inhibited by overexpression of mitochondrial transcription factor A (TFAM), the age-related decrease in LTP in CA1 is ameliorated (Hayashi et al, 2008), while eicosapentaenoic acid, which exerts anti-inflammatory and antioxidative effects similarly restores LTP in aged rats Martin et al, 2002).…”

Astrocytes and the Important Role in the Future Research of Brain

“…Mitochondrial transcription factor A (TFAM), is involved in mtDNA maintenance, including nucleotide formation, mtDNA stabilization and transcription [11]. Recent studies indicated that TFAM and PGC-1 over-expression may inhibit mitochondrial ROS generation and improve mitochondrial respiratory function [12,13]. Furthermore over-expression of TFAM has been shown to protect mitochondria against Aβ-induced oxidative damage in neurons [14].…”

“…First, as a member of the high-mobility group of protein, TFAM could cover the entire region of mtDNA to form the nucleoid structure, protecting mtDNA from oxidative or inflammation modifications [11,13]. Second, TFAM could maintain mtDNA copy number by binding mtDNA in the form of the nucleoid structure [21].…”