All ETDs from UAB

Advisory Committee Chair

Shannon M Bailey

Advisory Committee Members

Dale A Dickinson

Scott W Ballinger

Victor M Darley-Usmar

Aimee L Landar

Mathieu J Lesort

Document Type

Dissertation

Date of Award

2010

Degree Name by School

Doctor of Philosophy (PhD) School of Public Health

Abstract

Alcoholic liver disease is a serious public health concern. In particular, the mitochondrion is a specific target of ethanol toxicity and much of the damage can be related to unregulated Ca2+ homeostasis and oxidative stress which are key players in the induction of the mitochondrial permeability transition pore (MPTP) within the organelle. The mechanism behind the induction of the MPTP remains elusive. Therefore, this body of work will provide insight on what effects chronic alcohol consumption has on mitochondrial dysfunction with an emphasis on the MPTP. Chapter 2: Assessment of mitochondrial dysfunction arising from treatment with hepatotoxicants provides a description of several biochemical assays used to assess mitochondrial function when exposed to toxicants such as ethanol. Chapter 3: Chronic ethanol consumption enhances sensitivity to Ca2+-mediated opening of the mitochondrial permeability transition pore and increases cyclophilin D in liver presents data which test the hypothesis that chronic alcohol consumption causes mitochondrial dysfunction leading to increased sensitivity to the induction of the MPTP and impairment of Ca2+ retention capacity. The most significant findings were isolated liver mitochondria from ethanol-fed rats had decreased Ca2+ retention capacity, increased sensitivity to Ca2+-mediated induction of the MPTP, and increased levels of Cyclophilin D. Chapter 4: Cyclophilin D gene ablation is not protective against mitochondrial dysfunction in alcoholic liver disease extends and expands on the results presented in Chapter 3. This chapter further investigated the role of Cyp D in alcohol-induced mitochondrial injury using a Cyp D null mouse model. In this study we observed steatosis in livers of both wild-type and Cyp D-/- mice fed the ethanol-containing diet. State 4 respiration (ADP-independent) was increased in liver mitochondria isolated from both ethanol-fed wild-type and Cyp D-/- mice. Lastly, liver mitochondria from ethanol-fed Cyp D-/- were more sensitive than control-fed Cyp D-/- to Ca2+-mediated MPTP induction. These findings suggest that Cyp D gene ablation is not protective against alcohol induced mitochondrial dysfunction. Together this information provides a more comprehensive understanding of the molecular events that contribute to chronic ethanol-induced mitochondrial dysfunction and damage. An understanding of which we propose will better guide future therapeutic approaches for alcoholic liver disease. Key words: alcohol, liver, mitochondria, calcium, MPTP

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