MtDNA Damage and the Mitochondrial Theory of Aging

Despite the fact that in animal cells mtDNA comprises only 1 to 3% of the genetic material, it has been argued that its contribution to cellular physiology could be much greater than would be expected from its size alone. For instance:

1. It mutates at higher rates than nuclear DNA, which may be a consequence of its close proximity to the electron transfer chain (ETC).

2. It encodes either polypeptides of ETC or components required for their synthesis. Therefore, any coding mutations in mtDNA will affect the ETC as a whole. This could affect both the assembly and/or function of the products of numerous nuclear genes in ETC complexes.

3. Defects in the ETC can have pleiotropic effects because they affect cellular energetics as a whole.

Several lines of evidence indirectly implicate mtDNA in longevity. The Framingham Longevity Study of Coronary Heart Disease has indicated that longevity is more strongly associated with age of maternal death than that of paternal death, suggesting that mtDNA inheritance might be involved. On the other hand, longevity was shown to be associated with certain mtDNA polymorphisms. For instance, Italian male centenarians have an increased incidence of mtDNA haplogroup J, whereas French and Japanese centenarians have increased incidences of G to A transition at mt9055 and C to A transversion at mt5178, respectively. However, a study of an Irish population failed to link longevity to any particular mitochondrial haplotype, suggesting that factors other than mtDNA polymorphism also may play a role in aging (Ross et al., 2001).

Mitochondria have been shown to accumulate high levels of lipophilic carcinogens such as polycyclic aromatic hydrocarbons. When cells are exposed to some of these compounds, mtDNA is damaged preferentially. Other mutagenic chemicals, such as chromium (VI), N-methyl-N'-nitro-N-nitrosoguanidine (MNNG), 4-nitroquinoline 1-oxide (4NQO), and afla-toxin B1 also have been shown to preferentially target mtDNA. Therefore, it is conceivable that life-long exposure to certain environmental toxins could result in a preferential accumulation of mtDNA damage and accelerate aging. However, perhaps the most relevant kind of insult to which mtDNA is exposed is oxidative damage. The lack of protective histones and close proximity to the ETC, whose complexes I and III are believed to be the predominant sites for the reactive

î ROS production

ETC activity mtDNA transcription

Figure 41.2 "Vicious cycle'' during which ROS produced in ETC lead to the inhibition of mtDNA transcription and ETC activity, resulting in even higher levels of ROS production.

oxygen species (ROS) production inside the cell, make mtDNA extremely vulnerable to oxidative stress. Indeed, the free radical theory of aging states that it is the mitochondrial production of ROS and the resulting accumulation of damage to macromolecules that causes aging. Cumulative damage to biological macromolecules was proposed to overwhelm the capacity of biological systems to self-repair, resulting in an inevitable functional decline. The mitochondrial theory of aging can be considered as an extension and refinement of the free radical theory. Its major premise is that mtDNA mutations accumulate progressively during life, and are directly responsible for a measurable deficiency in cellular oxida-tive phosphorylation (OXPHOS) activity, leading to enhanced ROS production. In turn, increased ROS production results in an increased rate of mtDNA damage and mutagenesis, thus causing a ''vicious cycle'' of exponentially increasing oxidative damage and dysfunction that ultimately culminates in death (see Figure 41.2).

Since Miquel et al. first suggested that mtDNA might be damaged in aging (Miquel et al., 1980), numerous studies over the past two decades have provided a wealth of information consistent with the predictions of the free radical/mitochondrial theory of aging.

OXIDATIVE DAMAGE IN CELLS, AND IN PARTICULAR, IN mtDNA, IS UBIQUITOUS, SUBSTANTIAL, AND, LIKE MORTALITY RATES, INCREASES EXPONENTIALLY WITH AGE (SOHAL AND WEINDRUCH, 1996)

Exhalation of ethane and n-penthane, indicators of ROSmediated lipid peroxidation, increase with age. mtDNA was shown to accumulate oxidative damage in an age-dependent manner in skeletal muscle, the diaphragm, cardiac muscle, and the brain. Additionally, an age-related increase in oxidative damage to mtDNA appears to be more substantial than oxidative damage to nuclear DNA in houseflies. In rodents, an age-related increase in 7,8-dihydro-8-oxoguanine (8-oxodG), a mutagenic DNA

base lesion caused by oxidative stress, was observed in mtDNA isolated from the livers of both rats and mice (Hamilton et al., 2001). Dietary restriction, which is known to retard aging and increase the lifespan in rodents, has been found to significantly reduce the age-related accumulation of 8-oxodG levels in nDNA in all tissues of male B6D23F1 mice and in most tissues of male F344 rats. This study also showed that dietary restriction prevented the age-related increase in 8-oxodG levels in mtDNA isolated from the livers of both rats and mice (Hamilton et al., 2001). Another study found that the activities of the DNA repair enzymes for 8-oxoguanine, hypoxanthine, and uracil increase in liver extracts of Wistar and OXYS rats with age. In both strains, 8-oxoguanine DNA glycosylase (OGG1) activities were about 10 times greater in nuclear extracts than in mitochondrial extracts (Ishchenko et al., 2003). However, although OGG1 activity in nuclear extracts remained relatively constant throughout the study, this activity increased with age in mitochondrial extracts. Importantly, in OXYS rats, which are characterized by the overproduction of ROS, high levels of lipid peroxidation, protein oxidation, and decreased life span, the levels of mitochondrial OGG1 activity were greater than in normal Wistar rats, and an increase in this activity began earlier (Ishchenko et al., 2003). The increase in 8-oxodG levels in mtDNA with aging appears to be a general phenomenon and has been reported by several groups (Hudson et al., 1998; de Souza-Pinto et al., 2001). The steady-state concentration of 8-oxodG in mitochondrial DNA was shown to be inversely correlated with maximum lifespan (MLSP) in the heart and brain of mammals, such that slowly aging mammals show lower 8-oxodG levels in mtDNA than rapidly aging ones (Barja and Herrero, 2000). Furthermore, these authors show that this inverse relationship is restricted to mtDNA, due to the fact that 8-oxodG levels in nuclear DNA were not significantly correlated with MLSP. The correlation between 8-oxodG and MLSP was better in the heart and in the brain, possibly in part because these organs are composed predominantly of postmitotic cells (Barja and Herrero, 2000).

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