All ETDs from UAB

Advisory Committee Chair

Victor Darley-Usmar

Advisory Committee Members

Namasivayam Ambalavanan

Steven N Austad

Scott C Ballinger

Jennifer Pollack

C Roger White

Document Type

Dissertation

Date of Award

2022

Degree Name by School

Doctor of Philosophy (PhD) Heersink School of Medicine

Abstract

There is a differential susceptibility associated with several diseases including cardiovascular disease (CVD) and hypertension, with Blacks being more likely to develop these conditions. Blacks are also more likely to die from these diseases. To explain the genetic etiology underlying CVD pathogenesis, the primary focus has been on nuclear genetics-environmental interactions, whereas the contribution of mitochondrial genetics is less explored. Therefore, we sought to determine whether differences exist in cellular function and response to cell stress in healthy and diseased individuals with distinct mitochondrial genetic backgrounds. To determine this, we sought first to develop a technique to detect and quantify mtDNA DAMPS. To determine whether differences exist in a healthy population, we assessed bioenergetics and metabolomics in cord blood cells, and observed mtDNA DAMP and oxidant production in human umbilical vein endothelial cells (HUVECs) from healthy newborns with distinct mitochondrial genetic backgrounds. To determine whether differences exist in patients with disease, we assessed xanthine oxidase (XO) activity and mtDNA DAMP levels in black and white hypertensive and normotensive individuals. We hypothesized that differences would exist in the aforementioned parameters, with individuals with sub-Saharan mtDNAs having greater non-ATP linked respiration, increased ROS production, increased mtDNA DAMP production, and altered iv metabolomics as compared to those with north Eurasian mtDNAs. Additionally, we hypothesized that Blacks would exhibit increased XO activity and mtDNA DAMPs than Whites, and that individuals with resistant hypertension would have increased mtDNA DAMPs than normotensive controls. We were able to develop a technique that detects and quantifies mtDNA DAMPs in plasma, serum and cell culture media in humans and rodents that can easily be employed in other animal models. We also showed that individuals with sub-Saharan African mtDNAs have different bioenergetics, increased ROS, increased DAMPs, altered metabolomics, and increased XO activity than northern Eurasian mtDNAs. Overall, these data demonstrate that differences exist in cell function and response to cell stress based on mitochondrial genetic background. This data advances our knowledge of the role of mitochondria in cell function and innate immunity and add to our understanding of how mitochondrial genetics contribute to differential susceptibility to diseases like CVD and hypertension.

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