Age-dependent deficiency in import of mitochondrial DNA glycosylases required for repair of oxidatively damaged bases

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93 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)10670-10675
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume100
Issue number19
DOIs
StatePublished - Sep 16 2003

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DNA Glycosylases
Mitochondrial DNA
Mitochondria
Uracil-DNA Glycosidase
Liver Extracts
Mitochondrial Genome
Uracil
Mitochondrial Proteins
DNA Repair
Rodentia
Oxidative Stress
Fibroblasts
Mutation
Membranes
Liver
Enzymes
7,8-dihydro-8-oxoguanine

Keywords

  • 8-oxoguanine
  • Aging
  • DNA repair
  • Mitochondria
  • Oxidative stress

ASJC Scopus subject areas

  • Genetics
  • General

Cite this

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title = "Age-dependent deficiency in import of mitochondrial DNA glycosylases required for repair of oxidatively damaged bases",
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.",
keywords = "8-oxoguanine, Aging, DNA repair, Mitochondria, Oxidative stress",
author = "Bartosz Szczesny and Tapas Hazra and John Papaconstantinou and Sankar Mitra and Istvan Boldogh",
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T1 - Age-dependent deficiency in import of mitochondrial DNA glycosylases required for repair of oxidatively damaged bases

AU - Szczesny, Bartosz

AU - Hazra, Tapas

AU - Papaconstantinou, John

AU - Mitra, Sankar

AU - Boldogh, Istvan

PY - 2003/9/16

Y1 - 2003/9/16

N2 - 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.

AB - 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.

KW - 8-oxoguanine

KW - Aging

KW - DNA repair

KW - Mitochondria

KW - Oxidative stress

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