ROLE OF MTDNA DAMAGE IN ALCOHOL- AND CYP2E1-DEPENDENT TOXICITY

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This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. Alcoholic liver disease represents an important cause of death and disability in the United States. Acute and chronic ethanol consumption enhances oxidative stress in the liver, potentially leading to oxidative damage. Oxidative stress is characterized by an increased steady-state concentration of reactive oxygen species (ROS), which are oxidizing ions or molecules derived from the partial reduction of molecular oxygen. A central pathway by which ethanol generates a state of oxidative stress is the induction of the cytochrome P450 isoform 2E1 (CYP2E1), which metabolizes alcohol and generates ROS in the process. Ethanol causes liver mitochondrial DNA (mtDNA) oxidative damage and depletion, as well as mitochondrial dysfunction. In addition, prolonged alcohol administration induces a compensatory upregulation of mtDNA replication genes. However, the mechanisms of ethanol-induced mtDNA damage and imbalance and the extent to which mtDNA damage impairs mitochondrial function are currently unknown. Our long-term goal is to decipher the molecular events affecting mitochondria that result in alcohol-induced liver injury. Our objective is to identify the mechanisms and effects of mtDNA damage in alcohol-induced hepatocyte injury. The central hypothesis of this proposal is that high levels of ROS produced as a result of CYP2E1 activity and alcohol administration result in acute oxidative liver mtDNA damage followed by mitochondrial dysfunction and liver injury. Prolonged CYP2E1-dependent oxidative stress may result in compensatory increases in mtDNA replication, which may contribute to adaptation to ethanol after chronic exposure in vivo.