The hundreds of mitochondria present in every cell are critical to cell function. As the descendants of ancient symbiotic bacteria, mitochondria have their own remnant DNA, separate from the chromosomal genomic DNA present in the cell nucleus. Both sorts of DNA suffer similar forms of mutational damage and are attended by broadly similar repair mechanisms, but nuclear DNA is by far the better protected and maintained of the two. Some forms of mitochondrial DNA mutation, particularly the deletion of genes important to the electron transport chain, are thought to confer both dysfunction and competitive advantages to mitochondria, leading to a cell overtaken by broken mitochondria, exporting toxic reactive molecules into surrounding tissue. This may be important in aging, and in support of that proposition, researchers here find that longer lived mammalian species have a greater capacity for some forms of mitochondrial DNA repair.
Is the DNA repair of endogenous damage higher in long-lived animals? When base excision repair (BER) of genomic DNA was measured in four organs including heart and brain it was found not significantly changed or even decreased (instead of increased) in longer-lived caloric restricted mice. Moreover, comparative studies in brain and liver of 15 mammalian and avian species have shown that repair of genomic DNA endogenous oxidative damage by BER in nuclear fractions does not correlate with longevity or, more frequently, is lower (instead of higher) in tissues of long-lived mammals when compared to short-lived ones.
BER plays an important role in repairing oxidative damage to DNA, but these results might indicate that genomic (almost all nuclear) BER does not play a key role in longevity extension. The negative correlation of genomic DNA BER with longevity is analogous to what was previously found for the endogenous total cellular antioxidant enzymes CuZn SOD, catalase, glutathione peroxidase, and glutathione reductase, as well as reduced glutathione, which most generally negatively correlate, and in some cases do not significantly correlate with longevity in mammals and vertebrates.
The likely evolutionary explanation for this is that the mitochondrial ROS production rate (mitROSp) is also lower in long-lived than in short-lived animals. Since the mitochondria of long-lived animal species produce less H2O2 to the cytosol, they would also need less total cell endogenous antioxidants and less nuclear DNA repair systems. Endogenous total cell antioxidants and DNA repair enzymes are transitorily induced, when needed, to come back again to low levels when episodic increases in oxidative stress have been overcome. In this way, cells save much energy, which otherwise would be invested in the protein synthesis needed to continuously maintain high levels of cellular antioxidants and nuclear DNA repair enzymes when they are not needed at such high levels.
That is the situation concerning BER in nuclear DNA, but what occurs in the case of mitochondrial BER (mitBER)? MitBER had never been measured in species with different longevities, and we hypothesized that mitochondrial, instead of nuclear, BER is higher in long-lived than in short-lived mammals. We have thus recently measured activities and/or protein levels of various mitBER enzymes including DNA glycosylases, NTHL1 and NEIL2, and APE endonuclease in mitochondrial liver and heart fractions from eight mammalian species differing by 13-fold in longevity. Our results show, for the first time, a positive correlation between mitBER and mammalian longevity. This suggests that the low steady-state oxidative damage in mitDNA of long-lived species, not observed for nuclear DNA, can be due to the combination of a low rate of damage generation (low mitROSp) and a high level of mitDNA repair (by mitBER) in these slowly aging animals.