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ARS Home » Northeast Area » Boston, Massachusetts » Jean Mayer Human Nutrition Research Center On Aging » Research » Publications at this Location » Publication #166268
Title: ACCUMULATION OF MITOCHONDRIAL DNA DELETIONS IS AGE, TISSUE AND FOLATE-DEPENDENT IN RATS

Author
item CROTT, JIMMY - TUFTS-HNRCA
item CHOI, SANG-WOON - TUFTS-HNRCA
item BRANDA, RICHARD - UNIVERSITY OF VERMONT
item MASON, JOEL - TUFTS-HNRCA

Submitted to: Mutation Research
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 9/30/2004
Publication Date: 2/15/2005
Citation: Crott, J.W., Choi, S., Branda, R.F., Mason, J.B., 2005. Accumulation of mitochondrial DNA deletions is age, tissue and folate-dependent in rats. Mutation Research. 579(1):63-70.

Interpretive Summary: Folate is crucial in maintaining the health of our DNA. Folate depletion has been shown to cause DNA damage in cell culture, rodents and humans. We hypothesized that mitochondrial (Mt) DNA may also be sensitive to folate depletion and accumulate deletions due to DNA breakage. Mitochondrial deletions may play a role in carcinogenesis. Young and adult (12 month) rats consumed folate deplete, replete and supplemented diets (0, 2 and 8 mg/kg folate respectively) for 20 weeks. Damage to the mitochondrial genome was measured. Our results confirm that certain MtDNA deletions accumulate with age and that this effect is tissue specific. Furthermore, in contrast to previous work we report that the 4.8kb deletion is not modulated by age, but is reduced by folate supplementation in the liver of rats.

Technical Abstract: Folate is crucial in DNA synthesis, repair and methylation. Folate depletion causes genetic and epigenetic aberrations in cell culture, rodents and humans. We hypothesized that mitochondrial (Mt) DNA may also be sensitive to folate depletion and accumulate deletions due to DNA breakage. Mitochondrial deletions and mutations accumulate during aging and tumorogenesis and may play a causative role in these processes. Weanling and adult (12 month) Sprague Dawley rats consumed folate deplete, replete and supplemented diets (0, 2 and 8 mg/kg folate respectively) for 20 weeks. The presence of the common 4.8kb Mt deletion as well as random Mt deletions was measured in colonic mucosa and liver. With regard to random deletions, six short Mt genomes were detected in the liver (3.5 ' 7.0kb) and three in the colon (3.8 ' 8 kb). A significant effect of age was detected on random deletions in the liver; young and old rats had deletions present in 7.7% and 64% of samples respectively (P<0.0001). There was no effect of age on MtDNA deletions in the colon (3.1 and 7.7% in young and old respectively). Folate status had no effect on the development of random deletions in either tissue. In both tissues, no discrete effect of aging on the 4.8kb deletion was detected, however in the liver of old rats, increasing concentrations of folate reduced deletion frequency compared to baseline and deplete groups. Our results confirm that certain MtDNA deletions accumulate with age and that this effect is tissue specific. Furthermore, in contrast to previous work we report that the 4.8kb deletion is not modulated by age, but is reduced by folate supplementation in the liver of rats.