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Aging, The Molecular Concepts


While the level of somatic mtDNA mutations accumulates progressively in post-mitotic tissues with age, the level of somatic mtDNA mutations appears to be greatly elevated in certain degenerative diseases. In chronic ischemic heart disease resulting from atheroschlerosis of the coronary arteries, the levels of the 5 kb deletion have been found to be elevated between 7 and 2200 fold. Coronary artery disease causes cyclic ischemia and reperfusion as the partially occluded coronary artery contracts and expands. This results in cyclic bursts of ROS generation by the mitochondria (73). Hence, it seems likely that the increased mtDNA damage is the result of increased mtDNA ROS generation.

A comparable increase in somatic mtDNA damage has been observed in neurodegenerative disease. In Alzheimer's Disease (AD) brains, patients who died before the age of 75 had approximately 15 fold higher levels of the common 5 kb deletion in the cerebral cortex than aged-matched controls. By contrast, patients who died after age 75 had 5-fold less deletion than controls. This could be interpreted as indicating that AD patient brains may have a substantially elevated somatic mtDNA mutation rate, and when a cell's deletion level becomes sufficiently high, the cell dies and the deletions are lost (74).

An increased level of somatic mtDNA deletions was also found in Huntington's Disease (HD) brains. In HD patients who died prior to age 50, the 5 kb deletion was found to be elevated II fold in the temporal cortex and 5 fold in the frontal cortex. However, the 5 kb deletion was not elevated in basal ganglia, though this may reflect the dramatic cell loss in the basal ganglia of HD patients (75).

The most likely cause of somatic mtDNA mutations is ROS damage to the mtDNA. Not only are mtDNA rearrangements dramatically increased in ischemic heart disease, which is known to generate cyclic bursts of mitochondrial ROS, but the mtDNA has been found to accumulate 10 times more of the DNA oxidation production 8-hydroxy-21-deoxyguanosine (8-OhdG) than nDNA (76, 77). Furthermore, 8-OhdG accumulates in the mtDNA of a variety of tissues; with age (71, 76, 78). Hence, the accumulation of somatic mtDNA mutations with accompanying decline in mitochondrial energy production may be a common feature of both degenerative diseases and aging. Moreover, the cause of the mtDNA mutation is like to be mitochondrially generated ROS.

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