Oxidative Damage and Mutation to Mitochondrial DNA and Age‐dependent Decline of Mitochondrial Respiratory Function^a

Abstract

Mitochondrial respiration and oxidative phosphorylation are gradually uncoupled, and the activities of the respiratory enzymes are concomitantly decreased in various human tissues upon aging. An immediate consequence of such gradual impairment of the respiratory function is the increase in the production of the reactive oxygen species (ROS) and free radicals in the mitochondria through the increased electron leak of the electron transport chain. Moreover, the intracellular levels of antioxidants and free radical scavenging enzymes are gradually altered. These two compounding factors lead to an age-dependent increase in the fraction of the ROS and free radical that may escape the defense mechanism and cause oxidative damage to various biomolecules in tissue cells. A growing body of evidence has established that the levels of ROS and oxidative damage to lipids, proteins, and nucleic acids are significantly increased with age in animal and human tissues. The mitochondrial DNA (mtDNA), although not protected by histones or DNA-binding proteins, is susceptible to oxidative damage by the ever-increasing levels of ROS and free radicals in the mitochondrial matrix. In the past few years, oxidative modification (formation of 8-hydroxy-2'-deoxyguanosine) and large-scale deletion and point mutation of mtDNA have been found to increase exponentially with age in various human tissues. The respiratory enzymes containing the mutant mtDNA-encoded defective protein subunits inevitably exhibit impaired respiratory function and thereby increase electron leak and ROS production, which in turn elevates the oxidative stress and oxidative damage of the mitochondria. This vicious cycle operates in different tissue cells at different rates and thereby leads to the differential accumulation of mutation and oxidative damage to mtDNA in human aging. This may also play some role in the pathogenesis of degenerative diseases and the age-dependent progression of the clinical course of mitochondrial diseases.

Age-related impairment of human T lymphocytes’ activation: specific differences between CD4+ and CD8+ subsets

“…Previous studies on lymphocytes revealed an increase of reactive oxygen species (ROS) in aged subjects (Schindowski et al, 2000) or elevated by-products caused by ROS (e.g. lipidperoxidation (Hendricks and Heidrick, 1998), oxidized proteins (Stadtman, 1992;Berlett and Stadtman, 1997) and DNA-damage (Wei et al, 1998)). Altered and impaired signal transduction, in general, seems to be a major cause for impaired cellular function in all aged tissues (Eckert et al, 1994;Mü ller et al, 1996).…”

L‐carnitine inhibits hepatocarcinogenesis via protection of mitochondria

“…5 Thus, oxidative injury to mtDNA causes mutations in mitochondrial genes and/or results in the generation of abnormal proteins in the electron transport system. 6,7 Furthermore, mitochondrial membrane injury could also be induced via lipid peroxidation reactions in the presence of ROS. 8 Mitochondria are the major source of reactive oxygen species even in their normal state.…”

Origin of Nuclear Mitochondrial Pseudogenes (Numts)

“…Cells may break down mitochondria when they are not working properly or when it ages [9]. A lot of mitochondrial proteins are encoded in the nucleus.…”

“…Most likely, free radicals damage mitochondria causing release of components. A growing body of evidence has established that the levels of Reactive Oxygen Species and oxidative damage to lipids, proteins, and nucleic acids are significantly increased with age in animal and human tissues [9].…”