No evidence of mitochondrial respiratory dysfunction in OGG1-null mice deficient in removal of 8-oxodeoxyguanine from mitochondrial DNA.
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.
Stuart
J A
JA
Department of Biology, Brock University, St. Catharines, ON, Canada L2S 3A1.
Bourque
B M
BM
de Souza-Pinto
N C
NC
Bohr
V A
VA
D000080242:8-Hydroxy-2'-Deoxyguanosine; D000375:Aging; D000818:Animals; D045647:DNA Glycosylases / Q000235:genetics* / Q000502:physiology*; D004272:DNA, Mitochondrial / Q000378:metabolism*; D003849:Deoxyguanosine / Q000031:analogs & derivatives* / Q000235:genetics*; D005609:Free Radicals; D018698:Glutamic Acid / Q000378:metabolism; D006801:Humans; D008099:Liver / Q000378:metabolism; D008293:Malates / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D008928:Mitochondria / Q000378:metabolism / Q000473:pathology*; D008929:Mitochondria, Heart / Q000378:metabolism; D008930:Mitochondria, Liver / Q000378:metabolism; D009206:Myocardium / Q000378:metabolism; D018384:Oxidative Stress; D010100:Oxygen / Q000378:metabolism; D010101:Oxygen Consumption; D051381:Rats; D012120:Respiration Disorders / Q000235:genetics*; D013997:Time Factors
D004272:DNA, Mitochondrial; D005609:Free Radicals; D008293:Malates; D018698:Glutamic Acid; C030298:malic acid; D000080242:8-Hydroxy-2'-Deoxyguanosine; D045647:DNA Glycosylases; C485990:Ogg1 protein, mouse; D003849:Deoxyguanosine; D010100:Oxygen