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-1a (PGC-1a) 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-1a 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.