DEFECTIVE REPAIR OF OXIDATIVE DAMAGE IN MITOCHONDRIAL-DNA IN DOWNS-SYNDROME

Recent evidence indicates that oxidative DNA damage may be a major cau se of aging. One of the more sensitive targets is the mitochondrial ge nome which is 10 times more susceptible to mutation than is the nuclea r 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 neuron al tissues over time has been shown. In support of the notion that oxi dative stress leads to aging is the finding in Down's syndrome (DS), w hich is characterized by premature aging, that there is enhanced oxida tive stress resulting from the aberrant expression of CuZn superoxide dismutase (CuZn SOD). On the basis of these observations, we hypothesi zed that there may be defective repair of oxidative damage in mtDNA wh ich would ultimately lead to defective electron transport and concomit ant enhanced production of reactive oxygen species (ROS). This effect would heighten the oxidative burden in the cell and accelerate the dev elopment of phenotypes associated with aging. To evaluate repair of ox idative damage in mtDNA, fibroblasts from several DS patients were tre ated with the reactive oxygen generator menadione. Oxidative damage wa s assessed at 0, 2, and 6 h after exposure using a Southern-blot techn ique and a mtDNA specific probe. The results of these studies show tha t DS cells are impaired in their ability to repair oxidative damage to mtDNA compared to age-matched control cells. Therefore, this data sup ports the possibility that increased production of ROS from mitochondr ia plays a crucial role in the development of aging phenotypes. (C) 19 98 Elsevier Science B.V. All rights reserved.