Roles of mitochondrial DNA mutation and oxidative damage in human aging

One of the consequences of the age-dependent decline of respiratory function is the increase in the production of reactive oxygen species (ROS) and free radicals in mitochondria due to enhanced electron leak of the respiratory chain. It has been shown that the rate of production of superoxide anion and hydrogen peroxide in mitochondria increases with age. Moreover, the cellular levels of antioxidants and activities of free radical scavenging enzymes decrease during aging. These two concurrent events lead to an age-dependent increase of the oxidative stress, which may overwhelm the antioxidant defense system and cause oxidative damage to vital biomolecules in tissue cells. Abundant evidence now indicates that lipid peroxidation, protein modification, and DNA mutation are enhanced in aging tissues. The mitochondrial DNA (mtDNA) which is not protected by histones and yet exposed to ROS inside the mitochondria, is much more susceptible than nuclear DNA to oxidative insult during aging. In recent years, oxidative modification and mutation of mtDNA have been found to increase exponentially with age in human and animal tissues. The mutant mtDNA-encoded respiratory enzymes exhibit impaired respiratory function, and thereby increase the production of ROS and free radicals, which further elevate the oxidative stress and oxidative damage to mitochondria. In this article, we review the recent work pertaining to this 'vicious cycle' and discuss the role of mitochondria in human aging and age-related degenerative diseases.