NUTRITIONAL FACTORS THAT INFLUENCE DTMP SYNTHESIS AND MITOCHONDRIAL DNA INTEGRITY
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Folate and vitamin B12 deficiencies lead to megaloblastic anemia, fatigue, and neurological decline. Both folate and B12 are essential cofactors for the folate-mediated one carbon metabolism (FOCM). FOCM provides one carbon moieties for different cellular processes such as methionine regeneration and de novo dTMP synthesis. Folate deficiency is rare in the United States due to mandate fortification of the food chain, however, B12 deficiency is common in some populations like vegans/vegetarians, older adults, and people that use metformin. At the molecular level, either deficiency leads to impaired dTMP (thymidylate, the “T” base in DNA) and its precursor, dUMP (uracil, RNA base) to be misincorporated into DNA. In nDNA uracil misincorporation leads to genome instability and cell death. However, the biological consequences of uracil misincorporation have been predominantly studied in nuclear DNA not mitochondrial. MtDNA integrity is closely tied to energy production as it encodes for several components of the oxidative phosphorylation (OXPHOS) pathway. Previous work in liver has shown that impairments in FOCM lead to uracil misincorporation in mtDNA and impaired OXPHOS activity. This dissertation addresses several gaps in our knowledge of the relationship between folate and B12 in mtDNA integrity and mitochondrial function by focusing on energetic organs such as skeletal muscle, heart, and brain.