Is there more to aging than mitochondrial DNA and reactive oxygen species?

Abstract

Summary With the aging of the population, we are seeing a global increase in age-related disorders, especially in developed countries. Chronic diseases disproportionately affect the older segment of the population, contributing to disability, a diminished quality of life, and an increase in healthcare costs. Increased life expectancy reflects the success of contemporary medicine, which must now respond to the challenges created by this achievement, including the growing burden of chronic illnesses, injuries, and disabilities. A well-developed theoretical framework is required to understand the molecular basis of aging. This, in turn, is a prerequisite for developing the clinical interventions that will constitute an efficient response to the challenge of age-related health issues. This review critically analyzes the experimental evidence that supports and refutes the Free Radical/Mitochondrial Theory of Aging, which has dominated the field of aging research for almost half a century.

Mre11 is expressed in mammalian mitochondria where it binds to mitochondrial DNA

“…The presence even in unstressed cells is not surprising since mitochondria constantly produce ROS, an unavoidable byproduct of oxidative phosphorylation. Proximity to mtDNA could lead to the higher steady-state level of oxidative damage in mitochondrial, compared with nuclear, DNA (1,22,46). Oxidized DNA bases can be a source of DSBs for which function of Mre11 is well studied, because DSBs are generated by the collapse of replication forks when the replication machinery encounters the single-strand breaks that are intermediates in repair of oxidative damage (7).…”

“…The mitochondriaenriched fraction is contaminated with golgi and chromatin. mitochondria, and the ROS could damage their DNA (1,3,46). In our next experiments we tested those possibilities.…”

“…16). Also, accumulation of damage to the mitochondrial genome is central in the mitochondrial theory of aging (1,20,22). DNA repair serves to reduce accumulation of mutations in mtDNA, but the mechanisms of mtDNA repair are not nearly as well understood as those of nuclear DNA repair.…”

“…Since Mre11 is present in the proteome of yeast mitochondria (36), we suggested that it might also be present in mammalian mitochondria. Also, a possible role for Mre11 in mitochondria was suggested by observations that Mre11 binds to broken nuclear DNA and processes it for repair (40) and that mitochondria contain DNA (mtDNA) that is constantly being damaged by the reactive oxygen species (ROS) produced there (1,3,46). Mammalian mitochondria possess DNA repair pathways similar to those in the nucleus, namely base excision repair, mismatch repair, nonhomologous end joining, and homologous recombination (reviewed in Ref.…”

DNA ligase III

“…13 During this process, reactive oxygen species are produced as unavoidable byproducts 14 and have the potential to damage the mitochondrial genome. Several inherited diseases result from mutations in the mitochondrial The smallest eukaryal ligase known is Chlorella virus DNA ligase (ChVLig; 298 amino acids), consisting solely of a CC with conserved motifs found in the ATP-dependent ligases.…”