Excessive alcohol consumption leads to injury in many organ systems, including fatty changes and cirrhosis of liver, skeletal muscle myopathy, heart disease, pancreatitis, and changes in cognitive function. Although these pathological changes are well-documented, little is understood about the underlying molecular mechanisms. Many studies have shown that alcohol causes severe abnormalities in mitochondrial shape, ultrastructure, and respiratory activity. A promising avenue of future research, therefore, is mitochondrial dynamics, which has recently been demonstrated to control mitochondrial shape, ultrastructure, and function. There has been rapid progress in understanding the machineries that mediate mitochondrial fusion and fission, and we have developed mouse models to study the consequences of defective mitochondrial fusion. Mitochondrial fusion is controlled by two mitochondrial outer membrane GTPases called Mitofusin 1 and 2 (Mfn1 and Mfn2), and we have constructed mice with conditional alleles in both. We hypothesize that mitochondrial fusion protects cells from alcohol-induced injury and will use our mouse models to test this hypothesis in liver and muscle cells. Specifically, we will use mouse strains containing conditional alleles of Mfn1 and Mfn2 to determine whether loss of mitochondrial fusion increases susceptibility to alcohol-induced liver damage. In addition, we will use primary mouse myoblast cultures, derived from mice carrying conditional Mfn1 and Mfn2 alleles, to determine whether mitochondrial fusion is involved in skeletal muscle myopathy, one of the most common consequences of chronic alcohol use. Taken together, these experiments will examine the role of mitochondrial dynamics in two important tissues affected adversely by alcohol--the liver and skeletal muscle--and may lead to insights to develop new therapies. Statement of relevance to public health: Alcohol abuse is a major public health issue in the United States. Estimates from the National Council on Alcohol and Drug Dependence indicate that approximately 18 million Americans suffer from alcohol over-consumption. It is a major cause of mortality and results in enormous economic costs due to health care, crime, car accidents, and absence from work. It is known that alcohol damages mitochondria structure and activity in many tissue and organs, including the liver, skeletal muscle, heart, pancreas, and brain. However, we have little molecular understanding of the underlying cellular processes or pathways involved. Alcohol consumption has been shown to cause damage to mitochondria, and we will test whether mitochondrial fusion is an important factor. Basic biomedical research into the pathophysiology of disease has traditionally resulted in long-term benefits and may lead to effective therapies. If this research reveals that defects in mitochondrial dynamics play an important role in alcohol-mediated damage, it will contribute to our understanding of fundamental disease mechanisms and may lead to new treatments. ? ? ? ?
