Stuart JA, Bourque BM, de Souza-Pinto NC, Bohr VANo evidence of mitochondrial respiratory dysfunction in OGG1-null mice deficient in removal of 8-oxodeoxyguanine from mitochondrial DNA. Free Radic Biol Med 38:737-745

Department of Biology, Brock University, St. Catharines, ON, Canada L2S 3A1.
Free Radical Biology and Medicine (Impact Factor: 5.74). 04/2005; 38(6):737-45. DOI: 10.1016/j.freeradbiomed.2004.12.003
Source: PubMed


Accumulation of high levels of mutagenic oxidative mitochondrial DNA (mtDNA) lesions like 8-oxodeoxyguanine (8-oxodG) is thought to be involved in the development of mitochondrial dysfunction in aging and in disorders associated with aging. Mice null for oxoguanine DNA glycosylase (OGG1) are deficient in 8-oxodG removal and accumulate 8-oxodG in mtDNA to levels 20-fold higher than in wild-type mice (N.C. Souza-Pinto et al., 2001, Cancer Res. 61, 5378-5381). We have used these animals to investigate the effects on mitochondrial function of accumulating this particular oxidative base modification. Despite the presence of high levels of 8-oxodG, mitochondria isolated from livers and hearts of Ogg1-/- mice were functionally normal. No differences were detected in maximal (chemically uncoupled) respiration rates, ADP phosphorylating respiration rates, or nonphosphorylating rates with glutamate/malate or with succinate/rotenone. Similarly, maximal activities of respiratory complexes I and IV from liver and heart were not different between wild-type and Ogg1-/- mice. In addition, there was no indication of increased oxidative stress in mitochondria from Ogg1-/- mice, as measured by mitochondrial protein carbonyl content. We conclude, therefore, that highly elevated levels of 8-oxodG in mtDNA do not cause mitochondrial respiratory dysfunction in mice.

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Available from: Nadja C Souza-Pinto
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    • "Intriguingly, the resulting supraphysiological levels of genomic 8-oxoG did not affect embryonic development or life span. Moreover, increased levels of 8-oxoG in the mitochondrial DNA did not affect mitochondrial respiratory parameters or ROS production [11]. Under conditions of chronic oxidative stress, genomic 8-oxoG levels can be increased up to 250-fold in Ogg1 À / À mice, without apparent consequences, including precancerous lesions or tumors in various organs [12]. "
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    ABSTRACT: Reactive oxygen species inflict oxidative modifications on various biological molecules, including DNA. One of the most abundant DNA base lesions 8-oxo-7,8-dihydroguanine (8-oxoG) is repaired by 8-oxoguanine DNA glycosylase-1 (OGG1) during DNA base excision repair (OGG1-BER). 8-OxoG accumulation in DNA has been associated with various pathological and aging processes, while its role is unclear. The lack of OGG1-BER in Ogg1-/- mice resulted in decreased inflammatory responses, increased susceptibility to infections and metabolic disorders. Therefore, we proposed that OGG1 and/or 8-oxoG base may have a role in immune and homeostatic processes. To test our hypothesis, we challenged mouse lungs with OGG1-BER product 8-oxoG base and changes in gene expression were determined by RNA sequencing and data were analyzed by gene ontology and statistical tools. RNA-Seq analysis identified 1592 differentially expressed (≥ 3-fold change) transcripts. The upregulated mRNAs were related to biological processes, including homeostatic, immune-system, macrophage activation, regulation of liquid-surface tension, and response to stimulus. These processes were mediated by chemokines, cytokines, gonadotropin-releasing hormone receptor, integrin and interleukin signaling pathways. Taken together, these findings points to a new paradigm showing that OGG1-BER plays a role in various biological processes that may benefit host, but when is in excess could be implicated in disease and/or aging processes. Copyright © 2015. Published by Elsevier Inc.
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    • "Knockout mice lacking the BER enzyme DNA-oxodG-glycosylase (OGG1), displayed a 20-fold greater accumulation of 8-oxoGua Biogerontology (2014) 15:417–438 421 than control animals. Despite high levels of mtDNA damage, the cells of these mice were not significantly different from controls in either mitochondrial oxygen consumption or in the activity of ETC respiratory complexes (Stuart et al. 2005). This indicates a need for further investigation the significance of oxidative damage found in mtDNA (e.g., accumulation of 8-oxoGua in mtDNA) for mitochondrial function. "
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    ABSTRACT: We review the impact of mitochondrial DNA (mtDNA) maintenance and mitochondrial function on the aging process. Mitochondrial function and mtDNA integrity are closely related. In order to create a protective barrier against reactive oxygen and nitrogen species (RONS) attacks and ensure mtDNA integrity, multiple cellular mtDNA copies are packaged together with various proteins in nucleoids. Regulation of antioxidant and RONS balance, DNA base excision repair, and selective degradation of damaged mtDNA copies preserves normal mtDNA quantities. Oxidative damage to mtDNA molecules does not substantially contribute to increased mtDNA mutation frequency; rather, mtDNA replication errors of DNA PolG are the main source of mtDNA mutations. Mitochondrial turnover is the major contributor to maintenance of mtDNA and functionally active mitochondria. Mitochondrial turnover involves mitochondrial biogenesis, mitochondrial dynamics, and selective autophagic removal of dysfunctional mitochondria (i.e., mitophagy). All of these processes exhibit decreased activity during aging and fall under greater nuclear genome control, possibly coincident with the emergence of nuclear genome instability. We suggest that the age-dependent accumulation of mutated mtDNA copies and dysfunctional mitochondria is associated primarily with decreased cellular autophagic and mitophagic activity.
    Full-text · Article · Jul 2014 · Biogerontology
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    • "The assumption that any accumulation of molecular damage should be expected to lead to a functional loss and/or decrease in longevity is contradicted by the evidence that, owing to redundancy, relatively high threshold levels of DNA and protein oxidative damage are required for manifest losses in function [150]. For instance, OGG1-null mice exhibited relatively high concentrations of 8-OHdG, a DNA oxidation product, but showed no effect on survival [182] [185], suggesting that oxidative damage below a certain threshold may be only latently causal in functional decline [150]. The naked mole rat indeed presents an intriguing and potentially interesting model for studying an atypical pattern of aging, as it displays a relatively high steady-state level of oxidative stress/damage and an aberrant survivorship curve [165]. "
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