Research Project
9746138
ABSTRACT The overarching goal of this proposal is to elucidate the role that mitochondrial remodeling in the liver plays in alcoholic liver disease (ALD). Our recent exciting findings suggest that chronic alcohol feeding causes dynamic mitochondrial remodeling in the liver that enhances mitochondrial bioenergetic activity as an adaptation to alcohol. We observed two major types of mitochondrial remodeling following alcohol feeding: 1) increased biogenesis of key mitochondrial constituents (e.g. expression of respiratory complex proteins, pyridine nucleotide levels) and, 2) alterations in liver mitochondrial morphology through changes in mitochondrial fusion-fission rates. Our findings add new insights to the established dogma that ALD primarily involves mitochondrial dysfunction. While this paradigm of mitochondrial dysfunction in ALD has been widely accepted for decades, it represents an incomplete picture of mitochondrial dynamics in the liver. Chronic alcohol feeding causes some mitochondrial dysfunction, but it also induces a great deal of mitochondrial remodeling in the liver as an adaptation to the stress induced by alcohol intake. In this proposal, we will examine the significance of mitochondrial remodeling in ALD by modulating two distinct pathways in the liver. Peroxisome proliferator-activated receptor gamma coactivator-1? (PGC-1?) is the master regulator of mitochondrial biogenesis, and our preliminary data suggests that it plays a role in alcohol- induced mitochondrial biogenesis, particularly of respiratory complexes in the liver. Consequently, we will silence PGC-1? using antisense (ASO) to determine if mitochondrial biogenesis plays a beneficial (i.e. adaptation) or deleterious role in the liver with chronic alcohol feeding. During ALD, like in many pathologies, mitochondrial fusion-fission alters to increase mitochondrial heterogeneity, which produces subpopulations of mitochondria that may have different properties (respiration, reactive oxygen species generation, JNK binding). We will modulate mitochondrial fusion-fission rates using ASO (e.g. Mfn-2 - produces fragmented mitochondria; Opa-1 - produces larger mitochondria) to alter mitochondrial heterogeneity to determine its significance in the pathogenesis of ALD. The proposal has two specific aims: 1) Determine the significance of mitochondrial biogenesis in the pathogenesis of ALD, and 2) Determine the extent and significance of mitochondrial heterogeneity that occurs in the liver with alcohol feeding. Overall, by modulating two different aspects of mitochondrial remodeling (biogenesis and fusion-fission), our proposal should provide new insights on the role mitochondrial remodeling plays in ALD. Although our proposal focuses on alcohol, we believe the findings of this study will have broader implications in liver pathophysiology, since many liver diseases, such as non-alcoholic fatty liver disease, are also associated with mitochondrial remodeling.
