No evidence of mitochondrial respiratory dysfunction in OGG1-null mice deficient in removal of 8-oxodeoxyguanine from
J A Stuart1, B M Bourque, N C de Souza-Pinto
1Department of Biology, Brock University, St. Catharines, ON, Canada L2S 3A1.
Abstract:
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.
Insights
High levels of 8-oxodeoxyguanine (8-oxodG) in mitochondrial DNA (mtDNA) do not impair mitochondrial function. Studies using OGG1-deficient mice show normal respiration and oxidative stress despite accumulated 8-oxodG lesions.
Area of Science:
- Mitochondrial biology
- Oxidative stress and DNA damage
- Aging research
Background:
- Accumulation of oxidative lesions like 8-oxodeoxyguanine (8-oxodG) in mitochondrial DNA (mtDNA) is linked to aging and related disorders.
- Mice lacking oxoguanine DNA glycosylase (OGG1) accumulate significantly higher levels of 8-oxodG in mtDNA compared to wild-type mice.
Purpose of the Study:
- To investigate the functional consequences of accumulating 8-oxodG in mtDNA on mitochondrial respiration and oxidative stress.
- To determine if elevated 8-oxodG levels contribute to mitochondrial dysfunction.
Main Methods:
- Mitochondria were isolated from the livers and hearts of OGG1-deficient (Ogg1-/-) and wild-type mice.
- Mitochondrial respiratory function was assessed by measuring respiration rates (maximal, ADP-phosphorylating, non-phosphorylating).
- Activities of respiratory complexes I and IV were measured, and mitochondrial protein carbonyl content was used to assess oxidative stress.
Main Results:
- Mitochondria from Ogg1-/- mice showed no differences in maximal respiration rates or ADP-phosphorylating respiration compared to wild-type.
- Non-phosphorylating respiration rates and activities of respiratory complexes I and IV were also similar between the two groups.
- Mitochondrial protein carbonyl content, an indicator of oxidative stress, was not elevated in Ogg1-/- mice.
Conclusions:
- Highly elevated levels of 8-oxodeoxyguanine in mtDNA do not appear to cause mitochondrial respiratory dysfunction in mice.
- These findings suggest that other factors may be more critical in the development of age-related mitochondrial dysfunction.
- The study highlights the complex relationship between DNA damage and cellular function in aging.
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