Crott Jimmy W, Choi Sang-Woon, Branda Richard F, Mason Joel B
Vitamins and Carcinogenesis Laboratory, Jean Mayer USDA Human Nutrition Research Center on Aging at Tufts University, 711 Washington Street, Boston, MA 02111-3117, USA.
Mutat Res. 2005 Feb 15;570(1):63-70. doi: 10.1016/j.mrfmmm.2004.09.009.
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.
叶酸对于DNA的合成、修复及甲基化至关重要。叶酸缺乏会在细胞培养、啮齿动物及人类中导致核遗传和表观遗传异常。我们推测叶酸缺乏可能还会损害线粒体（Mt）DNA并因DNA断裂而诱导大规模缺失。MtDNA缺失和突变在衰老及肿瘤发生过程中会不断积累，并可能在这些过程中发挥致病作用。断乳及成年（12个月）的斯普拉格·道利大鼠分别食用叶酸缺乏、充足及补充型日粮（分别含0、2和8 mg/kg叶酸）20周。检测结肠黏膜和肝脏中随机及常见（4.8 kb）MtDNA缺失的存在情况。在肝脏中检测到6个含有随机缺失的Mt基因组（<16 kb）（3.5 - 7.0 kb），在结肠中检测到3个（3.8 - 8 kb）。老年大鼠肝脏中随机MtDNA缺失显著多于幼年大鼠（分别为样本的64%和3.2%，P<0.0001），而年龄对结肠中的这些缺失无影响（幼年和老年分别为3.1%和7.7%）。叶酸摄入量对任一组织中随机缺失的频率均无影响。衰老对肝脏或结肠中常见的4.8 kb缺失无明显影响。然而，在老年大鼠的肝脏中，增加日粮叶酸量可降低缺失频率，叶酸充足及补充型日粮组大鼠的缺失频率分别比缺乏组大鼠低2.2倍和3.2倍。我们的结果证实随机MtDNA缺失会随年龄增长以组织特异性方式积累。此外，与之前的研究不同，我们报告称常见的4.8 kb缺失不受年龄调节，但在大鼠肝脏中可通过补充叶酸而减少。
