Age-dependent deficiency in import of mitochondrial DNA glycosylases required for repair of oxidatively damaged bases
Year: 2003
Type: article
Abstract: The mitochondria are the major source of chronic oxidative stress, which has been implicated in the aging process. Along with other cellular changes, aged cells accumulate mutations in both their nuclear and mitochondrial genomes, and they contain increased amounts of oxidatively damaged mutagenic bases such as 7,8-dihydro-8-oxoguanine, suggesting age-dependent inhibition of its repair. Surprisingly, the level and activity of 8-oxoguanine-DNA glycosylase (OGG1), responsible for repair of 7,8-dihydro-8-oxoguanine, was found to be higher in the liver mitochondrial extract from old rodents than in that from young ones. We addressed this paradox by analyzing OGG1 in the mitochondria of young vs. old mouse livers, as well as in replicating vs. presenescent human fibroblasts. We show here that although the total OGG1 activity is higher in old mitochondria, a large fraction of the enzyme is stuck to the membrane in the precursor form, which could not be translocated to and processed in the mitochondrial matrix. A nearly identical phenomenon was observed with the mitochondrial uracil-DNA glycosylase responsible for repair of mutagenic uracil. These results indicate an age-dependent decline in the mitochondrial import of proteins needed for DNA repair and possibly for other functions.
Institution: The University of Texas Medical Branch at Galveston
Language: English
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: green
Awards: Cellular Response Mechanisms to Environmental Challenge, G1544950519, G2901611043, AGING EFFECTS ON MOLECULAR RESPONSES TO STRESS, G3119154873, G6588145764, Repair of Oxidized Bases in Mammalian Genomes, OXIDATIVE STRESS, APOPTOSIS AND DRUG RESISTANCE, Oxidative Stress, Mitochondrial Dysfunction and Aging, G838088, G853285647, UTMB Claude D. Pepper Older Americans Independence Center
OpenAlex ID: W1978946171