Defective repair of oxidative damage in mitochondrial DNA in Down's syndrome.
Recent evidence indicates that oxidative DNA damage may be a major cause of aging. One of the more sensitive targets is the mitochondrial genome which is 10 times more susceptible to mutation than is the nuclear genome. A number of age-related neuromuscular degenerative diseases also have been associated with mutations in mitochondrial DNA (mtDNA), and progressive accumulation of oxidative damage in mtDNA from neuronal tissues over time has been shown. In support of the notion that oxidative stress leads to aging is the finding in Down's syndrome (DS), which is characterized by premature aging, that there is enhanced oxidative stress resulting from the aberrant expression of CuZn superoxide dismutase (CuZn SOD). On the basis of these observations, we hypothesized that there may be defective repair of oxidative damage in mtDNA which would ultimately lead to defective electron transport and concomitant enhanced production of reactive oxygen species (ROS). This effect would heighten the oxidative burden in the cell and accelerate the development of phenotypes associated with aging. To evaluate repair of oxidative damage in mtDNA, fibroblasts from several DS patients were treated with the reactive oxygen generator menadione. Oxidative damage was assessed at 0, 2, and 6 h after exposure using a Southern-blot technique and a mtDNA specific probe. The results of these studies show that DS cells are impaired in their ability to repair oxidative damage to mtDNA compared to age-matched control cells. Therefore, this data supports the possibility that increased production of ROS from mitochondria plays a crucial role in the development of aging phenotypes.
Druzhyna
N
N
Department of Structural and Cellular Biology, University of South Alabama, Mobile 36688, USA.
Nair
R G
RG
LeDoux
S P
SP
Wilson
G L
GL
D001483:Base Sequence; D002478:Cells, Cultured; D002675:Child, Preschool; D004249:DNA Damage; D017931:DNA Primers; D004260:DNA Repair; D004272:DNA, Mitochondrial / Q000235:genetics*; D004314:Down Syndrome / Q000235:genetics*; D005260:Female; D006801:Humans; D007223:Infant; D008297:Male; D018384:Oxidative Stress
D017931:DNA Primers; D004272:DNA, Mitochondrial