Circulating cell-free mitochondrial DNA (cf-mtDNA) is an emerging biomarker of psychobiological stress and disease which predicts mortality and is associated with various disease states.
First, I present a systematic review of the literature that shows cf-mtDNA levels respond to common real-world stressors. The review discusses current knowledge on the mechanisms of cf-mtDNA release, its molecular forms of transport, potential physiological functions, cellular and neuroendocrine triggers, and factors that may contribute to cf-mtDNA removal from the circulation.
Second, to evaluate the contribution of cf-mtDNA to health and disease states, standardized high-throughput procedures are needed to quantify cf-mtDNA in relevant biofluids. I describe the development of MitoQuicLy: Mitochondrial DNA Quantification in cell-free samples by Lysis. I demonstrate high agreement between MitoQuicLy and a commonly used column-based method, although MitoQuicLy is faster, cheaper, and requires a smaller input sample volume. I find that cf-mtDNA levels between concurrently collected plasma, serum, and saliva from the same individual differ on average by up to two orders of magnitude and are poorly correlated with one another, pointing to different cf-mtDNA biology or regulation between commonly used biofluids in clinical and research settings.
Finally, I deploy MitoQuicLy in a highly phenotyped cohort of participants with mitochondrial disease and healthy controls to quantify the impact of a brief psychological stressor on cf-mtDNA levels in three biofluids and evaluate how cf-mtDNA release varies between individuals, biofluids, and mitochondrial disease status.
These studies set the stage for a research agenda identifying novel links between psychological stress and physiological response, which may improve our understanding of how stressful experiences increase disease risk. In the future, cf-mtDNA release or its downstream effects may be targeted to modulate the impact of psychological stress on human health.
| Identifer | oai:union.ndltd.org:columbia.edu/oai:academiccommons.columbia.edu:10.7916/0brx-8d56 |
| Date | January 2024 |
| Creators | Michelson, Jeremy |
| Source Sets | Columbia University |
| Language | English |
| Detected Language | English |
| Type | Theses |
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