Kensuke Tsushima1, Heiko Bugger1, Adam R Wende1, Jamie Soto1, Gregory A Jenson1, Austin R Tor1, Rose McGlauflin1, Helena C Kenny1, Yuan Zhang1, Rhonda Souvenir1, Xiao X Hu1, Crystal L Sloan1, Renata O Pereira1, Vitor A Lira1, Kenneth W Spitzer1, Terry L Sharp1, Kooresh I Shoghi1, Genevieve C Sparagna1, Eva A Rog-Zielinska1, Peter Kohl1, Oleh Khalimonchuk1, Jean E Schaffer1, E Dale Abel2. 1. From the Division of Endocrinology and Metabolism, Fraternal Order of Eagles Diabetes Research Center, Roy J. and Lucille A. Carver College of Medicine (K.T., J.S., G.A.J., A.R.T., R.M., H.C.K., Y.Z., R.S., R.O.P., E.D.A.) and Department of Health and Human Physiology (V.A.L.), University of Iowa, Iowa City; Division of Endocrinology, Metabolism, and Diabetes and Program in Molecular Medicine (K.T., H.B., A.R.W., J.S., X.X.H., C.L.S., E.D.A.), Nora Eccles Harrison Cardiovascular Research and Training Institute (K.W.S.), and Department of Biochemistry (O.K.), University of Utah School of Medicine, Salt Lake City; Cardiology and Angiology I (H.B.) and Institute for Experimental Cardiovascular Medicine (E.A.R.-Z., P.K.), Heart Center Freiburg University, and Faculty of Medicine (H.B., E.A.R.-Z., P.K.), University of Freiburg, Germany; Division of Molecular and Cellular Pathology, Department of Pathology, University of Alabama at Birmingham (A.R.W.); Department of Radiology (T.L.S., K.I.S.) and Diabetic Cardiovascular Disease Center, Cardiovascular Division (J.E.S.), Washington University School of Medicine, St. Louis, MO; Division of Cardiology, Department of Medicine, University of Colorado Anschutz Medical Center, Aurora (G.C.S.); and Department of Biochemistry and Nebraska Redox Biology Center, University of Nebraska, Lincoln (O.K.). 2. From the Division of Endocrinology and Metabolism, Fraternal Order of Eagles Diabetes Research Center, Roy J. and Lucille A. Carver College of Medicine (K.T., J.S., G.A.J., A.R.T., R.M., H.C.K., Y.Z., R.S., R.O.P., E.D.A.) and Department of Health and Human Physiology (V.A.L.), University of Iowa, Iowa City; Division of Endocrinology, Metabolism, and Diabetes and Program in Molecular Medicine (K.T., H.B., A.R.W., J.S., X.X.H., C.L.S., E.D.A.), Nora Eccles Harrison Cardiovascular Research and Training Institute (K.W.S.), and Department of Biochemistry (O.K.), University of Utah School of Medicine, Salt Lake City; Cardiology and Angiology I (H.B.) and Institute for Experimental Cardiovascular Medicine (E.A.R.-Z., P.K.), Heart Center Freiburg University, and Faculty of Medicine (H.B., E.A.R.-Z., P.K.), University of Freiburg, Germany; Division of Molecular and Cellular Pathology, Department of Pathology, University of Alabama at Birmingham (A.R.W.); Department of Radiology (T.L.S., K.I.S.) and Diabetic Cardiovascular Disease Center, Cardiovascular Division (J.E.S.), Washington University School of Medicine, St. Louis, MO; Division of Cardiology, Department of Medicine, University of Colorado Anschutz Medical Center, Aurora (G.C.S.); and Department of Biochemistry and Nebraska Redox Biology Center, University of Nebraska, Lincoln (O.K.). DRCadmin@uiowa.edu.
Abstract
RATIONALE: Cardiac lipotoxicity, characterized by increased uptake, oxidation, and accumulation of lipid intermediates, contributes to cardiac dysfunction in obesity and diabetes mellitus. However, mechanisms linking lipid overload and mitochondrial dysfunction are incompletely understood. OBJECTIVE: To elucidate the mechanisms for mitochondrial adaptations to lipid overload in postnatal hearts in vivo. METHODS AND RESULTS: Using a transgenic mouse model of cardiac lipotoxicity overexpressing ACSL1 (long-chain acyl-CoA synthetase 1) in cardiomyocytes, we show that modestly increased myocardial fatty acid uptake leads to mitochondrial structural remodeling with significant reduction in minimum diameter. This is associated with increased palmitoyl-carnitine oxidation and increased reactive oxygen species (ROS) generation in isolated mitochondria. Mitochondrial morphological changes and elevated ROS generation are also observed in palmitate-treated neonatal rat ventricular cardiomyocytes. Palmitate exposure to neonatal rat ventricular cardiomyocytes initially activates mitochondrial respiration, coupled with increased mitochondrial polarization and ATP synthesis. However, long-term exposure to palmitate (>8 hours) enhances ROS generation, which is accompanied by loss of the mitochondrial reticulum and a pattern suggesting increased mitochondrial fission. Mechanistically, lipid-induced changes in mitochondrial redox status increased mitochondrial fission by increased ubiquitination of AKAP121 (A-kinase anchor protein 121) leading to reduced phosphorylation of DRP1 (dynamin-related protein 1) at Ser637 and altered proteolytic processing of OPA1 (optic atrophy 1). Scavenging mitochondrial ROS restored mitochondrial morphology in vivo and in vitro. CONCLUSIONS: Our results reveal a molecular mechanism by which lipid overload-induced mitochondrial ROS generation causes mitochondrial dysfunction by inducing post-translational modifications of mitochondrial proteins that regulate mitochondrial dynamics. These findings provide a novel mechanism for mitochondrial dysfunction in lipotoxic cardiomyopathy.
RATIONALE: Cardiac lipotoxicity, characterized by increased uptake, oxidation, and accumulation of lipid intermediates, contributes to cardiac dysfunction in obesity and diabetes mellitus. However, mechanisms linking lipid overload and mitochondrial dysfunction are incompletely understood. OBJECTIVE: To elucidate the mechanisms for mitochondrial adaptations to lipid overload in postnatal hearts in vivo. METHODS AND RESULTS: Using a transgenic mouse model of cardiac lipotoxicity overexpressing ACSL1 (long-chain acyl-CoA synthetase 1) in cardiomyocytes, we show that modestly increased myocardial fatty acid uptake leads to mitochondrial structural remodeling with significant reduction in minimum diameter. This is associated with increased palmitoyl-carnitine oxidation and increased reactive oxygen species (ROS) generation in isolated mitochondria. Mitochondrial morphological changes and elevated ROS generation are also observed in palmitate-treated neonatal rat ventricular cardiomyocytes. Palmitate exposure to neonatal rat ventricular cardiomyocytes initially activates mitochondrial respiration, coupled with increased mitochondrial polarization and ATP synthesis. However, long-term exposure to palmitate (>8 hours) enhances ROS generation, which is accompanied by loss of the mitochondrial reticulum and a pattern suggesting increased mitochondrial fission. Mechanistically, lipid-induced changes in mitochondrial redox status increased mitochondrial fission by increased ubiquitination of AKAP121 (A-kinase anchor protein 121) leading to reduced phosphorylation of DRP1 (dynamin-related protein 1) at Ser637 and altered proteolytic processing of OPA1 (optic atrophy 1). Scavenging mitochondrial ROS restored mitochondrial morphology in vivo and in vitro. CONCLUSIONS: Our results reveal a molecular mechanism by which lipid overload-induced mitochondrial ROS generation causes mitochondrial dysfunction by inducing post-translational modifications of mitochondrial proteins that regulate mitochondrial dynamics. These findings provide a novel mechanism for mitochondrial dysfunction in lipotoxic cardiomyopathy.
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