All ETDs from UAB

Advisory Committee Chair

Victor M Darley-Usmar

Advisory Committee Members

John C Chatham

Yabing Chen

Louis J Dell'Italia

C Roger White

Document Type

Dissertation

Date of Award

2011

Degree Name by School

Doctor of Philosophy (PhD) Heersink School of Medicine

Abstract

The mitochondrion plays a central role in the maintenance of bioenergetic function through the production of ATP and essential metabolites. The development of mitochondrial bioenergetic defects is a hallmark of important pathologies such as cardiovascular and liver diseases. It is well established that a decrease in mitochondrial function, typically of 20-40%, is associated with the progression of these pathologies. Causal relationships have been more difficult to establish because of the challenge of assessing mitochondrial function in a cellular setting. Specifically, it is known that mitochondria function at less than their maximal respiratory capacity and the remainder, known as reserve or spare capacity, is thought to be utilized for increased work or combatting oxidative stress. The following questions have been addressed in this dissertation: 1) Does reserve capacity change under conditions of diminished oxygen availability?, 2) Do the variations in mitochondrial phenotype caused by differences in the mitochondrial DNA sequence amongst different populations modify the response to a pathological stress?, and 3) Does the metabolism of alcohol in the liver interact with the mitochondria to change reserve capacity and the response to nitric oxide and hypoxia? In testing these concepts, we have used in vivo models of alcoholic liver disease and cardiac volume overload and an ex vivo model of vascular ischemia/reperfusion. Taken together, our data support the concept that mitochondrial bioenergetics are a key determinant of the response of a wide variety of cells to pathological stressors.

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