The mitochondrial theory of aging suggests that DNA damage in the mitochondrial genome leads to dysfunction and production of reactive oxygen species implicated in the aging process. This DNA damage partly results from mutagenic base lesions in the form of 7,8-dihydro-8-oxoguanine (8-oxoG) and uracil. Cells normally utilize DNA glycosylases, such an 8-oxoguannine-DNA glycosylase (OGG1) and uracil-DNA glycosylase (UDG), in the first step of repairing such DNA damage. Aging produces high levels of 8-oxoG damage in mitochondrial DNA, but the levels and activity of OGG1 are higher in mitochondrial extracts from older rodents. In the September 1 PNAS, Bartosz Szczesny and colleagues at the University of Texas Medical Branch show that this apparent inconsistency is caused by a large fraction of OGG1 being caught in the mitochondrial membrane (PNAS, DOI:10.1073/pnas.1932854100, September 1, 2003).

Szczesny et al. analyzed OGG1 levels in the mitochondrial extracts of two different systems: 4- and 20-month-old mouse livers and a standard in vitro model consisting of replicating and presenescent MRC5 fibroblasts. Increased levels of OGG1 were found in the mitochondria of aged livers and presenescent MRC5 fibroblasts. But, in the aged liver and presenescent MRC5 cells, two distinct OGG1 bands—of approximately 45 and 47 kDa—were distinguished by Western blot. Mitochondrial OGG1 exists in a precursor (47 kDa) and mature (45 kDa) form, and these results implied that aged mitochondria contained more of the precursor form. The mature form of OGG1 is released after import into the mitochondria, suggesting that this import was malfunctioning in aged livers. To test this, the authors fractionated mouse liver mitochondria into an outer membrane /intermembrane space (OM/IMS) and inner matrix and determined that aged livers predominately contained the precursor form of OGG1 in the OM/IMS, while young livers contained mature OGG1 only in the inner matrix. The OGG1 in the OM/IMS of aged mitochondria was also increasingly sensitive to proteolytic cleavage (the precursor being much more sensitive to such cleavage than the mature form) when compared with OGG1 from young mitochondria. The authors obtained similar results with UDG, suggesting "a general phenomenon" of dysfunction during aging.

"These results indicate an age-dependent decline in the mitochondrial import of proteins needed for DNA repair," conclude the authors. These findings add further weight to the theory that mitochondria are key in the process of aging.