Date of Graduation
5-2026
Document Type
Thesis
Degree Name
Bachelor of Science in Chemistry
Degree Level
Undergraduate
Department
General Human Environmental Sciences
Advisor/Mentor
Joanna L. Fiddler
Committee Member
Margaret A. Hershberger
Second Committee Member
Amy R. Poe
Abstract
Folate, or vitamin B9, is an essential micronutrient that serves as a carrier of one-carbon (1C) units throughout the cell. Enzymes and folate co-enzymes facilitate the movement of 1C units through the metabolic network known as folate-mediated one-carbon metabolism (FOCM), which is vital in methylation reactions, DNA synthesis, and amino acid metabolism. FOCM is compartmentalized between the mitochondria, nucleus, and cytoplasm. Within the mitochondria, FOCM contributes to DNA synthesis either by 1) the generation of de novo thymidylate nucleotides for mitochondrial DNA (mtDNA) via a reaction catalyzed by mitochondrial serine hydroxymethyltransferase 2 (SHMT2), or 2) the production of formate for purine synthesis in the cytosol. SHMT2 is an essential enzyme that transfers a 1C unit from serine to tetrahydrofolate (THF), generating glycine and 5,10-methyleneTHF, a key one-carbon donor in both formate and thymidylate synthesis.
Previous research has indicated that mtFOCM impairment due to loss of Shmt2 or folate-depletion leaves liver mtDNA susceptible to uracil misincorporation and reduces mitochondrial respiration in mouse embryonic fibroblasts. Liver, skeletal muscle, and other highly oxidative tissues may be more sensitive to changes in SHMT2 expression and folate availability. Therefore, in vitro (wild-type or ΔSHMT2 C2C12 myoblast cells) and in vivo (Shmt2+/- and Shmt2+/+ C57Bl/6J mice) models of mtFOCM impairment were studied under folate-depleted or folate-adequate conditions. In the in vitro model of mtFOCM impairment, it was found that folate-depletion (FD) impairs cell growth in C2C12 myoblasts, though wild-type C2C12 myoblasts are able to compensate by increasing formate production in response to FD. In the in vivo model, plasma formate levels are reduced while liver formate levels are increased with loss of Shmt2. The results from in vivo formate analysis suggest that the liver may be prioritizing the use of mitochondrial 1C units for formate production over thymidylate production in mice with heterozygous loss of Shmt2, indicating a preference for whole-cell DNA synthesis over mtDNA-specific synthesis.
Keywords
Folate; Formate; Micronutrient Metabolism; Mitochondria; One-Carbon Metabolism
Citation
Nolan, C. G. (2026). Determining the Partitioning of One-Carbon Units in Impaired Mitochondrial Folate-Mediated One-Carbon Metabolism. Chemistry & Biochemistry Undergraduate Honors Theses Retrieved from https://scholarworks.uark.edu/chbcuht/75
