Accumulation of mitochondrial DNA deletions is age, tissue and folate-dependent in rats.
Folate is essential for the synthesis, repair and methylation of DNA. Folate depletion causes nuclear genetic and epigenetic aberrations in cell culture, rodents and humans. We hypothesized that folate depletion may also damage mitochondrial (Mt) DNA and induce large-scale deletions due to DNA breakage. MtDNA deletions and mutations accumulate during aging and tumorogenesis and may play causative roles in these processes. Weanling and adult (12 months) Sprague Dawley rats consumed folate deplete, replete and supplemented diets (0, 2 and 8 mg/kg folate, respectively) for 20 weeks. The presence of random and common (4.8 kb) MtDNA deletions was measured in colonic mucosa and liver. Six Mt genomes (<16 kb) harboring random deletions were detected in the liver (3.5-7.0 kb) and three in the colon (3.8-8 kb). Older rats had significantly more random hepatic MtDNA deletions than young rats (64 and 3.2% of samples, respectively, P<0.0001), while age had no effect on these deletions in the colon (3.1 and 7.7% in young and old, respectively). Folate intake had no effect on the frequency of random deletions in either tissue. There was no discrete effect of aging on the common 4.8 kb deletion in the liver or colon. However, in the liver of old rats, increasing amounts of dietary folate reduced the deletion frequency, with replete and supplemented rats having 2.2- and 3.2-fold less deletions than the depleted rats. Our results confirm that random MtDNA deletions accumulate with age in a tissue-specific fashion. Furthermore, in contrast to previous work, we report that the common 4.8 kb deletion was not modulated by age, but is reduced by folate supplementation in the liver of rats.
Crott
Jimmy W
JW
Vitamins and Carcinogenesis Laboratory, Jean Mayer USDA Human Nutrition Research Center on Aging at Tufts University, 711 Washington Street, Boston, MA 02111-3117, USA. jimmy.crott@tufts.edu
Choi
Sang-Woon
SW
Branda
Richard F
RF
Mason
Joel B
JB
D000367:Age Factors; D000818:Animals; D001483:Base Sequence; D003106:Colon / Q000378:metabolism; D004272:DNA, Mitochondrial / Q000378:metabolism; D005492:Folic Acid / Q000378:metabolism*; D008099:Liver / Q000378:metabolism; D008297:Male; D008928:Mitochondria / Q000235:genetics*; D009928:Organ Specificity; D051381:Rats; D017207:Rats, Sprague-Dawley; D017384:Sequence Deletion
D004272:DNA, Mitochondrial; D005492:Folic Acid