title: Decreasing mitochondrial fission alleviates hepatic steatosis in a murine model of nonalcoholic fatty liver disease.
abstract: Mitochondria produce the majority of cellular ATP through oxidative phosphorylation, and their capacity to do so is influenced by many factors. Mitochondrial morphology is recently suggested as an important contributor in controlling mitochondrial bioenergetics. Mitochondria divide and fuse continuously, which is affected by environmental factors, including metabolic alterations. Underscoring its bioenergetic influence, altered mitochondrial morphology is reported in tissues of patients and in animal models of metabolic dysfunction. In this study, we found that mitochondrial fission plays a vital role in the progression of nonalcoholic fatty liver disease (NAFLD). The development of hepatic steatosis, oxidative/nitrative stress, and hepatic tissue damage, induced by a high-fat diet, were alleviated in genetically manipulated mice suppressing mitochondrial fission. The alleviation of steatosis was recapitulated in primary hepatocytes with the inhibition of mitochondrial fission. Mechanistically, our study indicates that fission inhibition enhances proton leak under conditions of free fatty acid incubation, implicating bioenergetic change through manipulating mitochondrial fission. Taken together, our results suggest a mechanistic role for mitochondrial fission in the etiology of NAFLD. The efficacy of decreasing mitochondrial fission in the suppression of NAFLD suggests that mitochondrial fission represents a novel target for therapeutic treatment of NAFLD.
authors: Department of Anesthesiology, University of Rochester School of Medicine and Dentistry, Rochester, New York;
authors: Chad A
authors: CA
authors: Galloway
authors: Department of Physiology, Medical College of Georgia, Georgia Regents University, Augusta, Georgia.
authors: Hakjoo
authors: H
authors: Lee
authors: Department of Anesthesiology, University of Rochester School of Medicine and Dentistry, Rochester, New York;
authors: Paul S
authors: PS
authors: Brookes
authors: Department of Physiology, Medical College of Georgia, Georgia Regents University, Augusta, Georgia yyoon@gru.edu.
authors: Yisang
authors: Y
authors: Yoon
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D059305:Diet, High-Fat; D004195:Disease Models, Animal; D018450:Disease Progression; D004734:Energy Metabolism; D005234:Fatty Liver / Q000235:genetics / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology / Q000517:prevention & control*; D020022:Genetic Predisposition to Disease; D008099:Liver / Q000378:metabolism / Q000473:pathology* / Q000503:physiopathology; D051379:Mice; D057507:Mice, 129 Strain; D008822:Mice, Transgenic; D008930:Mitochondria, Liver / Q000378:metabolism / Q000473:pathology*; D063154:Mitochondrial Dynamics; D024101:Mitochondrial Proteins / Q000235:genetics / Q000378:metabolism; D009154:Mutation; D065626:Non-alcoholic Fatty Liver Disease; D018384:Oxidative Stress; D019308:Palmitic Acid / Q000378:metabolism; D013997:Time Factors; D014162:Transfection
chemical_list: D024101:Mitochondrial Proteins; D019308:Palmitic Acid
keywords: Dynamin-related protein 1; bioenergetics; mitochondrial morphology; oxidative stress; proton leak