Impact of vitamin B12 status on mitochondrial disease onset and progression

Mitochondrial function and cellular energy production are influenced strongly by maintenance of mitochondrial DNA (mtDNA). mtDNA depletion syndromes (MDS) result from inborn errors of metabolism (IEM) in mtDNA replication and repair enzymes. MDS are characterized by impaired mtDNA synthesis, mtDNA deletions, mitochondrial dysfunction, and severe multi-organ dysfunction phenotypes. However, the severity of the clinical features of MDS vary widely. There is also considerable heterogeneity in both the clinical presentation and age at onset for many MDS, even among individuals presenting with the same genetic mutations; this heterogeneity is believed to be driven by environmental and nutritional exposures. Maintenance of cellular thymidylate (dTMP) pools is essential for accurate DNA replication and for maintaining integrity of both mtDNA and nuclear DNA. Vitamin B12 (B12) is an essential cofactor required for de novo dTMP synthesis. B12 deficiency impairs de novo dTMP synthesis, leading to loss of DNA replication/repair fidelity and DNA damage. Our preliminary data indicates that mtDNA is more sensitive to B12 deficiency than is nuclear DNA and that B12 deficiency causes mtDNA damage, which then impairs mitochondrial energy production. MtDNA damage and impaired energy production are hallmarks of MDS. Understanding the role of B12 in MDS is important because B12 deficiency is common in older adults, vegans/vegetarians, and is a side-effect of commonly prescribed pharmaceuticals. Our central hypothesis is that B12 deficiency acts as a “second hit” to further impair mtDNA stability and exacerbate mitochondrial impairment and energy production in MDS. Ultimately, we hypothesize that B12 deficiency contributes to heterogeneity of onset and clinical presentation in MDS. The principal objectives of the proposed work are to: 1) define molecular mechanisms whereby B12 deficiency affects mtDNA stability biomarkers, mitochondrial function, and muscle strength in a mouse model of MDS, and 2) determine the role of B12 supplementation in mitigating adverse outcomes in MDS. Because mtDNA integrity declines with aging, the findings are likely to be relevant not only to individuals with IEM leading to MDS but also to older individuals and those affected by chronic disease. Project Number: 1R21AG100723-01 | Fiscal Year: 2026 | NIH Institute/Center: National Institute on Aging (NIA) | Principal Investigator: Martha Field | Institution: CORNELL UNIVERSITY, ITHACA, NY | Award Amount: $440,900 | Activity Code: R21 | Study Section: Nutrition and Metabolism in Health and Disease Study Section[NMHD] View on NIH RePORTER: https://reporter.nih.gov/project-details/11350000