Mitochondrial base excision repair positively correlates with longevity in the liver and heart of mammals

Abstract

Damage to DNA is especially important for aging. High DNA repair could contribute, in principle, to lower such damage in long-lived species. However, previous studies showed that repair of endogenous damage to nuclear DNA (base excision repair, BER) is negatively or not correlated with mammalian longevity. However, we hypothesize here that mitochondrial, instead of nuclear, BER is higher in long-lived than in short-lived mammals. We have thus measured activities and/or protein levels of various BER enzymes including DNA glycosylases, NTHL1 and NEIL2, and the APE endonuclease both in total and mitochondrial liver and heart fractions from up to eight mammalian species differing by 13-fold in longevity. Our results show, for the first time, a positive correlation between (mitochondrial) BER and mammalian longevity. This suggests that the low steady-state oxidative damage in mitochondrial DNA of long-lived species would be due to both their lower mitochondrial ROS generation and their higher mitochondrial BER. Long-lived mammals do not need to continuously maintain high nuclear BER levels because they release less mitROS to the cytosol. This can be the reason why they tend to show lower nuclear BER values. The higher mitochondrial BER of long-lived mammals contributes to their superior longevity, agrees with the updated version of the mitochondrial free radical theory of aging, and indicates the special relevance of mitochondria and mitROS for aging. Keywords Mitochondria. DNA repair. AP endonuclease. DNA glycosylases. Aging Abbreviations APE1 Apurinic/apyrimidinic endonuclease BER Base excision repair DR Dietary restriction mtDNA Mitochondrial DNA nDNA Nuclear DNA NTHL1 Endonuclease III homolog 1 NEIL2 Nei-like 2 5OHC 5-Hydroxycytosine

Alginate oligosaccharide alleviates D‐galactose‐induced cardiac ageing via regulating myocardial mitochondria function and integrity in mice

“…In addition to these mechanisms, recent study has also shown that lower mitochondrial ROS generation contributes to produce a low level of mtDNA steady‐state damage. 49 A higher mitochondrial base excision repair (BER) and a low mitochondrial damage of long‐live mammals in general contributes to their superior longevity. A recent report shows that NADPH oxidase inhibitor represses mitochondrial dysfunction in the ventral cochlear nucleus of D‐gal‐induced ageing rats 50 .…”

Higher DNA repair in mitochondria of long-lived species

“…Analogously, in long-lived animal species the BER enzyme levels are now known to be higher inside mitochondria than in the nucleus, and perhaps enzymatic and non-enzymatic antioxidants are present also at much higher levels inside mitochondria than at the cytosol. In any case, the recently described higher mitBER of long-lived mammals [ 5 ] seems to contribute to their superior longevity and constitutes a further piece of evidence indicating the special relevance of mitochondria and oxidative stress for the determination of species longevity.…”

“…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 [ 5 ]. Our results show, for the first time, a positive correlation between mitBER and mammalian longevity.…”

Role of the mtDNA Mutations and Mitophagy in Inflammaging

“…On the final step, 5 flap is cleaved by FEN-1 protein and ligated with DNA ligase III. Mitochondrial BER significantly contributes to longevity determination in mammals [31]. -Damaged mitochondrial proteins could be repaired and refolded back to their native state.…”