Changes in Mitochondrial DNA Deletion, Content, and Biogenesis in Folate-Deficient Tissues of Young Rats Depend on Mitochondrial Folate and Oxidative DNA Injuries

• Published in: The Journal of nutrition Vol. 137; no. 9; pp. 2036 - 2042
• Main Authors: Chou, Yi-Fang, Yu, Chu-Ching, Huang, Rwei-Fen S
• Format: Journal Article
• Language: English
• Published: Bethesda, MD American Society for Nutrition 01.09.2007; American Society for Nutritional Sciences
• Subjects: Aging - physiology; animal models; animal tissues; Animals; biogenesis; Biological and medical sciences; DNA Damage - genetics; DNA, Mitochondrial - biosynthesis; DNA, Mitochondrial - genetics; experimental diets; Feeding. Feeding behavior; folic acid; Folic Acid - metabolism; Fundamental and applied biological sciences. Psychology; Gene Deletion; genetic techniques and protocols; Homocysteine - blood; mitochondria; Mitochondria - genetics; Mitochondria - metabolism; mitochondrial DNA; nutrient reserves; nutrition assessment; oxidation; Oxidation-Reduction; oxidative stress; Rats; Rats, Wistar; RNA, Messenger - genetics; Vertebrates: anatomy and physiology, studies on body, several organs or systems; vitamin deficiencies; Nutrition; Rat; Injury; Rodentia; Mitochondrial DNA; Folic acid; Folate; Micronutrient; Tissue; Vertebrata; Mitochondria; Mammalia; Animal; Deletion
• ISSN: 0022-3166; 1541-6100
• DOI: 10.1093/jn/137.9.2036

We aimed to characterize folate-related changes in mitochondrial (mt) DNA of various tissues of young rats. Weaning Wistar rats were fed folate-deficient (FD) or folate-replete (control) diet for 2 or 4 wk. The mtDNA 4834-bp large deletion (mtDNA⁴⁸³⁴ deletion) and mtDNA content were analyzed by quantitative real-time PCR. Compared with pooled 2-wk and 4-wk control groups, 4-wk folate deprivation significantly increased the frequency of the mtDNA⁴⁸³⁴ deletion in pancreas, heart, brain, liver, and kidney and reduced mtDNA contents in brain, heart, and liver (P < 0.05). Decreased mt folate levels were correlated with increased mtDNA⁴⁸³⁴ deletion frequency in tissues from FD rats after 2 wk (r = -0.380, P = 0.001) and 4 wk FD (r = -0.275, P = 0.033) and with reduced mtDNA content after 4 wk (r = 0.513, P = 0.005). In liver of 4-wk FD rats, the accumulated mtDNA large deletions and decline in mtDNA accompanied increased expressions of messenger RNAs (mRNA) of factors that regulate mtDNA proliferation and transcription, including nuclear respiratory factor 1, mt transcriptional factor A, mt single-strand DNA-binding protein, and mt polymerase r. In parallel, expression of mRNA for nuclear-encoded cytochrome c oxidase subunits (CcOX) IV, V, cytochrome c, and mtDNA-encoded CcOX III increased significantly. This enhanced mt biogenesis in 4-wk FD liver coincided with an elevated ratio of 8 hydroxydeoxyguanosine (8-OHdG):deoxyguanosine (dG) (2.67 ± 1.41) relative to the controls (0.99 ± 0.36; P = 0.0002). The 8-OHdG:dG levels in FD liver were correlated with liver mt folate (r = -0.819, P < 0.001), mtDNA deletions (r = 0.580, P = 0.001), and mtDNA contents (r = -0.395, P = 0.045). Thus, folate deprivation induced aberrant changes of mtDNA⁴⁸³⁴ deletion and mtDNA content in a manner that was dependent on mt folate and oxidative DNA injuries. The folate-related mt biogenesis provides a molecular mechanism to compensate mtDNA impairment in FD tissues.