The basal levels of 8-oxoG and other oxidative modifications in intact mitochondrial DNA are low even in repair-deficient (Ogg1−/−/Csb−/−) mice

Trapp, Christian; McCullough, Amanda K.; Epe, Bernd

doi:10.1016/j.mrfmmm.2007.06.006

Cited by 22 publications

(22 citation statements)

References 51 publications

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“…Using this assay, there were no measurable differences in mtDNA amplification between WT and Ogg1 -/- mice in skeletal muscle DNA (Fig 3A). These results are consistent with previous reports suggesting tissue-specific differences in accumulation and repair of oxidative DNA damage [9,52,53]. The lack of difference between WT and Ogg1 -/- mice is also supportive of the existence of backup repair mechanisms or alternative methods of dilution or elimination of mtDNA damage in skeletal muscle [9,54,55].…”

Section: Resultssupporting

confidence: 92%

8-oxoguanine DNA glycosylase (OGG1) deficiency elicits coordinated changes in lipid and mitochondrial metabolism in muscle

et al. 2017

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Oxidative stress resulting from endogenous and exogenous sources causes damage to cellular components, including genomic and mitochondrial DNA. Oxidative DNA damage is primarily repaired via the base excision repair pathway that is initiated by DNA glycosylases. 8-oxoguanine DNA glycosylase (OGG1) recognizes and cleaves oxidized and ring-fragmented purines, including 8-oxoguanine, the most commonly formed oxidative DNA lesion. Mice lacking the OGG1 gene product are prone to multiple features of the metabolic syndrome, including high-fat diet-induced obesity, hepatic steatosis, and insulin resistance. Here, we report that OGG1-deficient mice also display skeletal muscle pathologies, including increased muscle lipid deposition and alterations in genes regulating lipid uptake and mitochondrial fission in skeletal muscle. In addition, expression of genes of the TCA cycle and of carbohydrate and lipid metabolism are also significantly altered in muscle of OGG1-deficient mice. These tissue changes are accompanied by marked reductions in markers of muscle function in OGG1-deficient animals, including decreased grip strength and treadmill endurance. Collectively, these data indicate a role for skeletal muscle OGG1 in the maintenance of optimal tissue function.

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Section: Resultssupporting

confidence: 92%

8-oxoguanine DNA glycosylase (OGG1) deficiency elicits coordinated changes in lipid and mitochondrial metabolism in muscle

et al. 2017

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“…To date, only a limited set of these have been specifically detected in mtDNA, but most are suspected to occur in mitochondria due to the oxidative conditions of the matrix [5,13,29,30,40–52] (Table 1). It has been known for over a decade that the steady-state level of oxidative damage in mtDNA is higher than that in nDNA; however, detection methods for oxidative lesions have required improvements to prevent artifacts and to allow the necessary specificity and sensitivity for measurements [53].…”

Section: Mitochondrial Dna Damagementioning

confidence: 99%

“…Together, they rectify most of the prevalent forms of free radical induced oxidative DNA damage. In fact, the level of 8-oxo-dG in the intact mtDNA isolated from the liver of OGG1 −/− mice is only slightly elevated above that in mtDNA from the liver of wild type animals, suggesting the efficient removal of 8-oxo-dG by the NEIL enzymes or the degradation of highly damaged mitochondrial chromosomes in the absence of OGG1 [30]. While mitochondria have redundant glycosylase activity for 8-oxo-dG removal, they appear to lack the monofunctional N-methylpurine DNA glycosylase, MPG, that is responsible for the BER processing of alkylpurines, including methylated bases and larger alkylations, such as the l, N 6 -etheno-dA and l, N 2 -etheno-dG adducts generated by reactive aldehydes [157–159].…”

Section: Mitochondrial Dna Repair Mechanismsmentioning

confidence: 99%

“…The CSB protein has been implicated in the repair of 8-oxo-dG, and the loss of CSB in an Ogg1 −/− background increases mutation rates [187, 188]. However, Ogg1 −/− Csb −/− mice have no significant increase in 8-oxo-dG in their liver mtDNA relative to wild type animals [30]. The NEIL glycosylases in mitochondra likely compensate for Ogg1 loss in removing 8-oxo-dG, and the elevated mutation frequencies with CSB loss may be due to the persistence of other oxidative lesions.…”

Section: Mitochondrial Dna Repair Mechanismsmentioning

confidence: 99%

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Mitochondrial DNA damage and its consequences for mitochondrial gene expression

Cline

2012

Biochimica et Biophysica Acta (BBA) - Gene Regulatory Mechanism

170

141

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How mitochondria process DNA damage and whether a change in the steady-state level of mitochondrial DNA damage (mtDNA) contributes to mitochondrial dysfunction are questions that fuel burgeoning areas of research into aging and disease pathogenesis. Over the past decade, researchers have identified and measured various forms of endogenous and environmental mtDNA damage and have elucidated mtDNA repair pathways. Interestingly, mitochondria do not appear to contain the full range of DNA repair mechanisms that operate in the nucleus, although mtDNA contains types of damage that are targets of each nuclear DNA repair pathway. The reduced repair capacity may, in part, explain the high mutation frequency of the mitochondrial chromosome. Since mtDNA replication is dependent on transcription, mtDNA damage may alter mitochondrial gene expression at three levels: by causing DNA polymerase γ nucleotide incorporation errors leading to mutations, by interfering with the priming of mtDNA replication by the mitochondrial RNA polymerase, or by inducing transcriptional mutagenesis or premature transcript termination. This review summarizes our current knowledge of mtDNA damage, its repair, and its effects on mtDNA integrity and gene expression.

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“…Although these results indicate a connection between BER and CSB, other evidence have suggested this may not be the case. For example, Csb m/m /Ogg1 −/− double transgenic mice do not accumulate more oxidative mitochondrial DNA damage than WT as measured using an assay where supercoiled mtDNA was relaxed after incision by the oxidative DNA damage specific endonuclease FPG (Trapp et al 2007). This view has recently been corroborated using long range qPCR showing no increased mitochondrial DNA damage in CSB deficient cells compared to controls (Berquist et al 2012).…”

Section: Cockayne Syndrome and Base Excision Repairmentioning

confidence: 99%

Mitochondrial deficiency in Cockayne syndrome

Scheibye‐Knudsen

Croteau

Bohr

2013

Mechanisms of Ageing and Development

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Cockayne syndrome is a rare inherited disorder characterized by accelerated aging, cachectic dwarfism and many other features. Recent work has implicated mitochondrial dysfunction in the pathogenesis of this disease. This is particularly interesting since mitochondrial deficiencies are believed to be important in the aging process. In this review, we will discuss recent findings of mitochondrial pathology in Cockayne syndrome and suggest possible mechanisms for the mitochondrial dysfunction.

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The basal levels of 8-oxoG and other oxidative modifications in intact mitochondrial DNA are low even in repair-deficient (Ogg1−/−/Csb−/−) mice

Cited by 22 publications

References 51 publications

8-oxoguanine DNA glycosylase (OGG1) deficiency elicits coordinated changes in lipid and mitochondrial metabolism in muscle

8-oxoguanine DNA glycosylase (OGG1) deficiency elicits coordinated changes in lipid and mitochondrial metabolism in muscle

Mitochondrial DNA damage and its consequences for mitochondrial gene expression

Mitochondrial deficiency in Cockayne syndrome

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