Simultaneous increase of mitochondrial DNA deletions and lipid peroxidation in human aging

Human mtDNA is a naked circular double-stranded DNA, which is continually exposed to the matrix that contains high levels of ROS and free radicals. High oxidative stress and a lack of proofreading during mtDNA replication and efficient DNA repair mechanisms in the mitochondria have rendered mtDNA extremely vulnerable to oxidative damage. More than one dozen large-scale deletions in mtDNA have been identified in various tissues of old humans. The 4977-bp and 7436-bp deletions are the most prevalent and abundant ones. The onset age of various mtDNA deletions varies greatly with tissues of each individual and type of deletion. In this and previous studies, we have demonstrated with PCR techniques that the frequency of occurrence and the proportion of the 4977-bp and 7436-bp deleted mtDNAs are significantly increased with the age of the human. The mtDNA deletions are not detectable in any tissues from young healthy subjects or blood cells from normal individuals of any age, which indicates that the deletions are generated and accumulated only in postmitotic cells upon aging. Moreover, we found that these mtDNA deletions occur more frequently and abundantly in tissues with high energy demand (e.g., muscle) as compared to those with low energy demand. On the other hand, we found that the amount of lipid peroxides measured as malondialdehyde and the activity of manganese-superoxide dismutase in the mitochondria exhibit an age-dependent increase in various human tissues. The lipid peroxide level in muscle was significantly higher than that in the other tissues. Moreover, we found a positive correlation between the proportion of the 4977-bp deleted mtDNA and lipid peroxide content in the mitochondria of human tissues during aging. Muscle, the tissue of high energy demand, was found to be more vulnerable to oxidative damage that lead to most abundant mtDNA deletions and lipid peroxidation among all the tissues examined. Taking these results together, we suggest that the enhanced generation of reactive oxygen species and lipid peroxides in the mitochondria during the aging process occur simultaneously with large-scale deletions and the other types of mutations in mtDNA, which are early molecular events and major contributory factors of human aging.