Date of Graduation
School of Medicine
The mitochondrion, a small but ubiquitously distributed organelle in the cell, continues to be the focus of many disease pathogeneses, tissue and organ dysfunctions, and other morbidities that occur throughout the body. The purpose of this work was to understand how cardiac mitochondrion are altered in disease and pathological states, specifically in their adaptation to environmentally stimulated regulatory networks, such as epigenetic modifications and promotion/inhibition of non-coding RNAs. Acute stress to mitochondrial regulation (inhalation toxicology) as well as chronic (type 2 diabetes mellitus) was examined. Using a FVB transgenic microRNA-378a mouse knockout model, the cardiovascular impact derived from altering the innate microRNA-378a response following acute nano-TiO2 inhalation exposure was evaluated. In atrial tissue from 50 patients (30 non-diabetic and 20 type 2 diabetic) physiological, biochemical, genomic, and epigenomic factors were assessed using machine learning algorithms in an attempt to better predict the pathogenesis of the disease in the heart. Next-generation sequencing was performed on human patient and FVB mouse mitochondrial and cytoplasmic non-coding RNA populations, along with polynucleotide phosphorylase (PNPase) crosslinking immunoprecipitation (CLIP). Ultimately, the work summarized in the preceding experiments highlights how multiple pathological insults, whether chronic or acute, can influence the underlying molecular, regulatory networks in the heart. While overt cardiovascular and mitochondrial dysfunction follow insult, an emphasis on epigenetic control and non-coding RNA regulation may prove to be primary axes for therapeutic intervention. As we continue to pursue more informed and predictive assessments of cardiovascular dysfunction, the mitochondrion remains at the heart of the issue.
Hathaway, Quincy Alexander, "Environmental Regulation of the Heart: The Role of Non-Coding RNA and Epigenetics in Influencing Mitochondrial and Cellular Health" (2019). Graduate Theses, Dissertations, and Problem Reports. 4052.