All ETDs from UAB

Advisory Committee Chair

Victor M Darley-Usmar

Advisory Committee Members

Anupam Agarwal

Scott Ballinger

Dale Dickinson

Aimee Landar

Document Type


Date of Award


Degree Name by School

Doctor of Philosophy (PhD) Heersink School of Medicine


Mitochondria are responsible for most of the energy produced in human tissues, and this is dependent on the reduction of oxygen (O2) to water by the mitochondrial respiratory chain. Defects in mitochondrial energy production are now recognized to be involved in diabetes, cancer, cardiovascular disease, and other pathologies. To date, studies of these defects have employed quantification of O2 consumption in isolated, purified mitochondria. By using this strategy however, the cellular context, role of glycolysis, and normal regulation of mitochondrial function by metabolite availability are lost. Thus, an understanding of how mitochondria function and respond to stimuli in an intact cellular context remains poorly understood. In this thesis, we used a new technology to examine mitochondrial and glycolytic bioenergetic pathways in intact, adherent cells. Interestingly, we found that all cell types consume O2 under basal conditions and possess a substantial ability to increase O2 consumption which we have quantified and termed the reserve capacity. This new understanding of O2 consumption in intact cells led to the hypothesis that the reserve capacity is depleted during cell stress resulting in death. To test this hypothesis, cells were treated with nitric oxide (NO) or 4-hydroxynonenal (HNE), two compounds relevant to the progression of cardiovascular disease. Using endothelial cells, we found that the reserve capacity was decreased in response to both acute and chronic treatment with NO, though the mechanism leading to this decrease differed with time of exposure. Likewise, the reserve capacity was decreased in response to HNE in isolated cardiomyocytes, and this occurred through yet another mechanism. Additionally, these data indicate the importance of the reserve capacity in response to secondary oxidant stressors. Following non-toxic NO treatment in endothelial cells, we demonstrated that secondary oxidative stress exceeded the bioenergetic capacity, and resulted in cell death. Together, these data suggest a novel role for cellular bioenergetics in the control of cell function and indicate that the reserve capacity is an important parameter which modulates the response to oxidant stress. These data also imply that increasing the reserve capacity may be an effective therapeutic strategy extending beyond cardiovascular disease to all cellular bioenergetic derangements.



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