Other Free Encyclopedias » Medicine Encyclopedia » Aging Healthy - Part 1 » Dna Damage and Repair - Dna Damage, Base Modifications In Dna After Exposures, Detection Of Dna Damage, Consequences Of Dna Damage

Dna Damage and Repair - Mitochondrial Dna Repair In Mammalian Cells

aging mtdna oxidative enzymes ber

Mitochondria are the energy stations inside the cells. Here, oxidative phosphorylation occurs, generating adenosine triphosphate (ATP). In this process, reactive oxygen species are formed at high frequencies, and the mitochondrial DNA (mtDNA) is directly exposed. The mitochondrial DNA does not have a recognized chromatin structure and thus is particularly exposed to formation of oxidative DNA base lesions.

There are about one thousand mitochondria per mammalian cell. Each mitochondrion has four to five DNA plasmids. This means that about 2 percent of total human DNA is in the mitochondria. All mtDNA is transcribed, whereas only about 1 percent of the nuclear DNA is transcribed. Thus the mtDNA makes up a large fraction of the total transcribed DNA in a mammalian cell.

MtDNA does not code for any DNA damage-processing enzymes. Thus, all repair enzymes functioning in the mitochondria need to be transported into them. It has been shown that mitochondria do not repair UV-induced lesions; this observation provided the basis for the notion that there is no DNA repair capacity in mtDNA. There have been many observations indicating the presence of BER in mitochondria. BER enzymes have been identified and characterized, and studies have shown that a number of oxidative DNA base lesions are efficiently removed from mtDNA. Other repair processes have also been detected (see Croteau et al. and other articles in the same issue of Mutation Research). An important question remaining is whether mitochondria possess any capabilities to repair bulky lesions via the NER pathway.

Knowledge about mtDNA repair is limited because it has been very difficult to study. Experimental techniques and methods have not been nearly as well developed as those for the study of nuclear DNA repair. Whereas in vitro repair studies have been performed with great success on nuclear or whole cell extracts from cells, this kind of biochemical approach has only very recently become available for mtDNA. Recent advances suggest that mtDNA repair can now be studied using more sophisticated biochemical analysis (Stierum et al.), and this should provide great advances in the near future.

Oxidative phosphorylation in mitochondria (which produces ATP) results in the production of reactive oxygen species (ROS). Other processes that contribute significantly to the pool of ROS include heat, ultraviolet light, drugs such as those used in the treatment of HIV, and ionizing radiation. Hydrogen peroxide, singlet oxygen, and hydroxyl radicals are among the ROS produced. The interactions between ROS and mtDNA result in oxidation of specific mtDNA bases, and such base modifications have been detected in human cells. Thus, insufficient mtDNA repair may result in mitochondrial dysfunction and thereby cause degenerative diseases, loss of energy formation, and pathophysiological processes leading to aging and cancer.

Identification of BER enzymes in mitochondria. Early indications for a BER mechanism in mitochondria came with the isolation of a mammalian mitochondrial endonuclease which specifically recognizes AP sites and cleaves the DNA strand. Later, it was demonstrated that a combination of enzymes purified from Xenopus laevis (a frog) mitochondria efficiently repair abasic sites in DNA.

The isolation of mitochondrial glycosylases has provided further evidence for a BER mechanism in mitochondria. Endonucleases specific for oxidative damage (mtODE), and for thymine glycols have been purified from rat mitochondria (Croteau et al., 1999).

The molecular mechanisms that lead to aging in multicellular organisms are still unclear. Many theories have arisen to explain the aging process, and among them the mitochondrial theory of aging, described earlier, has received much attention.

Dna Damage and Repair - Age-related Changes In Dna Repair [next] [back] Dna Damage and Repair - Dna Repair

User Comments

The following comments are not guaranteed to be that of a trained medical professional. Please consult your physician for advice.

Your email address will be altered so spam harvesting bots can't read it easily.
Hide my email completely instead?

Cancel or