SEARCH

SEARCH BY CITATION

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.