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Not quite a ‘carbon copy’: investigating the relationship between mitochondrial DNA heteroplasmy and one-carbon metabolism.

Walsh, Darren orcid logoORCID: 0000-0002-1239-0267 (2022) Not quite a ‘carbon copy’: investigating the relationship between mitochondrial DNA heteroplasmy and one-carbon metabolism. PhD thesis, Dublin City University.

One-carbon metabolism is a complex network of metabolic reactions that are essential for cellular function. Both vitamin B12 and folate are required for some of these important reactions to take place. Deficiency in either of these micronutrients and subsequent perturbation of one-carbon metabolism can cause erroneous DNA replication and repair to occur. This effect has been well characterised in nuclear DNA but to-date, mitochondrial DNA (mtDNA) has not been investigated extensively. The presence of mitochondrial DNA variations/mutations within a cell, tissue or organism is called mitochondrial heteroplasmy. Heteroplasmic variants have been associated with a number of inherited and age-related disease states and therefore the study of factors that impact heteroplasmy are important for furthering our understanding of the mitochondrial genome’s impact on human health. Heteroplasmy studies require robust and efficient mitochondrial DNA enrichment in order to carry out mtDNA sequencing. Current methods for mtDNA enrichment typically used in the field introduce biases and false positives. This thesis describes the adaption, characterisation and validation of a suitable sequence-independent enrichment method for mtDNA enrichment. This methodology was then utilised to sequence the mitochondrial DNA from mouse models of altered one-carbon metabolism. B12 deficiency was found to cause increased levels of mitochondrial DNA heteroplasmy across all tissues that were investigated. This impact was observed in two different studies using both wild-type and genetically modified mice. Folic acid supplementation also contributed to elevated mitochondrial DNA heteroplasmy across all mouse tissues investigated. Heteroplasmy analysis of human data from the Framingham Heart Study suggested a potential sex-specific effect of folate and B12 status on mitochondrial heteroplasmy. This is a novel relationship that may have broader consequences for our understanding of the mechanisms that drive onecarbon metabolism and mitochondrial related disease.
Item Type:Thesis (PhD)
Date of Award:November 2022
Supervisor(s):Parle-McDermott, Anne, Harold, Denise and Brody, Lawrence
Uncontrolled Keywords:Nutrition; Folic acid; B12; Mitochondrial heteroplasmy; Ageing
Subjects:Biological Sciences > Genetics
Biological Sciences > Bioinformatics
DCU Faculties and Centres:DCU Faculties and Schools > Faculty of Science and Health > School of Biotechnology
Funders:Wellcome Trust (205950/A/17/Z), National Human Genomics Research Institute, US, NIH Intramural Sequencing Centre, US, NIH Office of Dietary Supplements, US, OxCam program, US
ID Code:27480
Deposited On:15 Nov 2022 13:54 by Anne Parle-Mcdermott . Last Modified 15 Nov 2022 13:54

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