All ETDs from UAB

Advisory Committee Chair

Scott W Ballinger

Advisory Committee Members

Victor Darley-Usmar

Robert Fischer

Barbara Gower

Martin Young

Document Type


Date of Award


Degree Name by School

Doctor of Philosophy (PhD) Heersink School of Medicine


Obesity and cardiometabolic pathologies have reached epidemic levels worldwide over the last 30 years. Currently, the majority of research investigating possible genetic causes of obesity is focused on nuclear DNA (nDNA). While this has lead to the development of numerous animal models, it is apparent the etiology of obesity is more complex than single gene mutations. Recently it has also been suggested that mitochondrial DNA (mtDNA) mutations sustained during evolution as a consequence of our prehistoric environment may influence individual propensity and risk of disease. Contemporary human populations are no longer faced with the challenges of our ancestors such as sustained high activity and food scarcity. Instead, activity levels are comparatively low and calories are abundant. A mitochondrial-based approach to studying obesity and metabolic disease also makes sense in the context of differential disease susceptibility. The documented racial disparity in obesity and cardiovascular disease is consistent with the geographic variation observed in mtDNA. Interestingly, C57BL6/J mice are susceptible to numerous pathologies including diet-induced cardiovascular disease whereas C3H/HeN mice are resistant. These strains also have distinct mtDNAs, and thus, it is hypothesized that mtDNA mutations impact factors known to contribute to obesity and CVD such as mitochondrial economy, body composition and metabolic efficiency. To test this hypothesis, wild type and Mitochondrial-Nuclear eXchange (MNX) mice were exposed to chow or high-fat diet while housed in closed-air metabolic cages. After 6 weeks, there were significant differences in weight, metabolism and body composition and some of these differences segregate with mtDNA. Mice harboring C57 mtDNA showed increased weight gain and fat deposition, whereas C3H mtDNA was protective during high fat diet challenge. Additionally, myocardial metabolism and functional recovery following ischemia were altered in mice harboring non-native mtDNA, suggesting that mtDNA can influence expression of multiple nuclear metabolic genes. Overall, these results suggest that mtDNA directly impacts both whole body and organ-specific metabolism. Data herein demonstrates mitochondrial genetic effects on disease and provides new insights into a distinct, "mitochondrial-Mendelian" genetic basis of disease development.



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